| 1. |
- Mondal, Tanmoy, 1981, et al.
(author)
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MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- Long noncoding RNAs (lncRNAs) regulate gene expression by association with chromatin, but how they target chromatin remains poorly understood. We have used chromatin RNA immunoprecipitation-coupled high-throughput sequencing to identify 276 lncRNAs enriched in repressive chromatin from breast cancer cells. Using one of the chromatin-interacting lncRNAs, MEG3, we explore the mechanisms by which lncRNAs target chromatin. Here we show that MEG3 and EZH2 share common target genes, including the TGF-β pathway genes. Genome-wide mapping of MEG3 binding sites reveals that MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements. MEG3 binding sites have GA-rich sequences, which guide MEG3 to the chromatin through RNA–DNA triplex formation. We have found that RNA–DNA triplex structures are widespread and are present over the MEG3 binding sites associated with the TGF-β pathway genes. Our findings suggest that RNA–DNA triplex formation could be a general characteristic of target gene recognition by the chromatin-interacting lncRNAs.
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| 2. |
- Ali, Mohamad Moustafa, et al.
(author)
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PAN-cancer analysis of S-phase enriched lncRNAs identifies oncogenic drivers and biomarkers
- 2018
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
-
Journal article (peer-reviewed)abstract
- Despite improvement in our understanding of long noncoding RNAs (lncRNAs) role in cancer, efforts to find clinically relevant cancer-associated lncRNAs are still lacking. Here, using nascent RNA capture sequencing, we identify 1145 temporally expressed S-phase-enriched lncRNAs. Among these, 570 lncRNAs show significant differential expression in at least one tumor type across TCGA data sets. Systematic clinical investigation of 14 Pan-Cancer data sets identified 633 independent prognostic markers. Silencing of the top differentially expressed and clinically relevant S-phase-enriched lncRNAs in several cancer models affects crucial cancer cell hallmarks. Mechanistic investigations on SCAT7 in multiple cancer types reveal that it interacts with hnRNPK/YBX1 complex and affects cancer cell hallmarks through the regulation of FGF/FGFR and its downstream PI3K/AKT and MAPK pathways. We also implement a LNA-antisense oligo-based strategy to treat cancer cell line and patient-derived tumor (PDX) xenografts. Thus, this study provides a comprehensive list of lncRNA-based oncogenic drivers with potential prognostic value.
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| 3. |
- Ma, Haixia, et al.
(author)
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The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes
- 2023
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 299:6
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Journal article (peer-reviewed)abstract
- In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate pro-duction despite normal oxygen levels and functional mito-chondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is in-dependent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immu-noprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.
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| 4. |
- Mahale, Sagar, et al.
(author)
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HnRNPK maintains single strand RNA through controlling double-strand RNA in mammalian cells.
- 2022
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Although antisense transcription is a widespread event in the mammalian genome, double-stranded RNA (dsRNA) formation between sense and antisense transcripts is very rare and mechanisms that control dsRNA remain unknown. By characterizing the FGF-2 regulated transcriptome in normal and cancer cells, we identified sense and antisense transcripts IER3 and IER3-AS1 that play a critical role in FGF-2 controlled oncogenic pathways. We show that IER3 and IER3-AS1 regulate each other's transcription through HnRNPK-mediated post-transcriptional regulation. HnRNPK controls the mRNA stability and colocalization of IER3 and IER3-AS1. HnRNPK interaction with IER3 and IER3-AS1 determines their oncogenic functions by maintaining them in a single-stranded form. hnRNPK depletion neutralizes their oncogenic functions through promoting dsRNA formation and cytoplasmic accumulation. Intriguingly, hnRNPK loss-of-function and gain-of-function experiments reveal its role in maintaining global single- and double-stranded RNA. Thus, our data unveil the critical role of HnRNPK in maintaining single-stranded RNAs and their physiological functions by blocking RNA-RNA interactions.
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| 5. |
- Matthieu, Meryet-Figuiere, et al.
(author)
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Temporal separation of replication and transcription during S-phase progression.
- 2014
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In: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 13:20, s. 3241-3248
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Journal article (peer-reviewed)abstract
- Transcriptional events during S-phase are critical for cell cycle progression. Here, by using a nascent RNA capture assay coupled with high-throughput sequencing, we determined the temporal patterns of transcriptional events that occur during S-phase. We show that genes involved in critical S-phase-specific biological processes such as nucleosome assembly and DNA repair have temporal transcription patterns across S-phase that are not evident from total RNA levels. By comparing transcription timing with replication timing in S-phase, we show that early replicating genes show increased transcription late in S-phase whereas late replicating genes are predominantly transcribed early in S-phase. Global anti-correlation between replication and transcription timing was observed only based on nascent RNA but not total RNA. Our data provides a detailed view of ongoing transcriptional events during the S-phase of cell cycle, and supports that transcription and replication are temporally separated.
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| 6. |
- Mitra, Sanhita, et al.
(author)
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Subcellular distribution of p53 by the p53-responsive lncRNA NBAT1 determines chemotherapeutic response in neuroblastoma.
- 2021
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In: Cancer research. - 1538-7445. ; 81:6, s. 1457-1471
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Journal article (peer-reviewed)abstract
- Neuroblastoma has a low mutation rate for the p53 gene. Alternative ways of p53 inactivation have been proposed in neuroblastoma, such as abnormal cytoplasmic accumulation of wild-type p53. However, mechanisms leading to p53 inactivation via cytoplasmic accumulation are not well investigated. Here we show that the neuroblastoma risk-associated locus 6p22.3-derived tumor suppressor NBAT1 is a p53-responsive lncRNA that regulates p53 subcellular levels. Low expression of NBAT1 provided resistance to genotoxic drugs by promoting p53 accumulation in cytoplasm and loss from mitochondrial and nuclear compartments. Depletion of NBAT1 altered CRM1 function and contributed to the loss of p53-dependent nuclear gene expression during genotoxic drug treatment. CRM1 inhibition rescued p53-dependent nuclear functions and sensitized NBAT1-depleted cells to genotoxic drugs. Combined inhibition of CRM1 and MDM2 was even more effective in sensitizing aggressive neuroblastoma cells with p53 cytoplasmic accumulation. Thus, our mechanistic studies uncover an NBAT1-dependent CRM1/MDM2-based potential combination therapy for high-risk neuroblastoma patients.
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| 7. |
- Mondal, Tanmoy, 1981, et al.
(author)
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Chromatin RNA Immunoprecipitation (ChRIP).
- 2017
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In: Methods in molecular biology. - New York, NY : Humana Press. - 1940-6029. - 9781493973798 ; , s. 65-76
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Book chapter (peer-reviewed)abstract
- Researchers have recently had a growing interest in understanding the functional role of long noncoding RNAs (lncRNAs) in chromatin organization. Accumulated evidence suggests lncRNAs could act as interphase molecules between chromatin and chromatin remodelers to define the epigenetic code. However, it is not clear how lncRNAs target chromatin remodelers to specific chromosomal regions in order to establish a functionally distinct epigenetic state of chromatin. We developed and optimized chromatin RNA immunoprecipitation (ChRIP) technology to characterize the lncRNAs associated with active and inactive chromatin compartments. Use of ChRIP to identify chromatin-bound lncRNA will further improve our knowledge regarding the functional role of lncRNAs in establishing epigenetic modifications of chromatin.
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| 8. |
- Mondal, Tanmoy, 1981, et al.
(author)
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Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
- 2018
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3
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Journal article (peer-reviewed)abstract
- Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
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| 9. |
- Pandey, Gaurav Kumar, et al.
(author)
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The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation.
- 2014
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In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 26:5, s. 722-737
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Journal article (peer-reviewed)abstract
- Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.
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| 10. |
- Subhash, Santhilal, 1987
(author)
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Chromatin and transcriptome-based integrative approaches to profile functional long noncoding RNAs - A computational approach
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- One of the major hallmarks of cancer is aberrant or uncontrollable cell division, which occurs due to a defective cell cycle process. During the synthesis phase (S-phase) of the cell cycle, before cell division or mitosis phase, the DNA in the cell makes a new copy to pass on genetic information to the daughter cells. Therefore, S-phase is one of the crucial steps for a successful cell division to occur. The DNA in the nucleus is wrapped around a set of proteins called histones, forming nucleosomes, and multiple nucleosomes give rise to the higher-order chromatin structure. This well-established chromatin structure determines which portion of DNA or gene gets activated or suppressed by switching between open or closed chromatin states. Tri- or di-methylation of lysine 4 from histone 3 (H3K4me2/3) leads to open chromatin, which in turn promotes active gene transcription. The product of gene transcription is either protein-coding mRNA that translates into protein for its function or noncoding RNA, which do not code for any protein and function as RNA. However, the human genome project has identified that protein-coding genes only constitute 2% of the genome, and the vast majority of it is noncoding. Unlike protein-coding genes, the significance of RNAs transcribed from the noncoding genome is not well-established. Apart from housekeeping noncoding RNAs (rRNA, tRNA, snRNA, and snoRNA) and microRNAs (miRNAs), most functional noncoding RNAs fall into the long noncoding RNA (lncRNA) category. In this thesis, we implemented comprehensive computational approaches to identify functionally relevant lncRNAs by analyzing chromatin and transcriptome-based sequencing datasets. In the first study (paper I), using a transcriptome approach, we profiled lncRNAs associated with the S-phase stage of the cell cycle. We demonstrated the oncogenic properties of various S-phase associated lncRNAs in multiple cancers. Earlier, studies proposed that chromatin-associated RNAs, with the help of chromatin-modifying enzymes, determines the active/open or close chromatin status to promote or suppress gene transcription. Hence, in the second study (paper II), we used chromatin-based approaches to propose a possible mechanism through which the active chromatin- associated lncRNAs may function. We show that active chromatin-associated lncRNAs regulate their partner genes in-cis by recruiting the WDR5 chromatin modifier to establish an open chromatin structure at the partner protein-coding gene promoters. In our third study (paper III), we integrated both transcriptome and chromatin-based approaches to find early development-associated lncRNAs. Here, we focused on tracing the molecular footprints of sperm lncRNAs throughout the stages of organismal development. For this purpose, we integrated datasets from gametes, preimplantation and post-implantation stages of an embryo. Interestingly, we observed distinct chromatin structures in the sperm. Also, sperm lncRNAs were active during the onset of zygotic genome activation in the preimplantation stages and in cancers. In summary, this study reveals a unique set of sperm-specific lncRNAs that are temporally activated during preimplantation stages and also aberrantly expressed in multiple cancers. Overall, the present thesis provides an extensive catalogue of functionally relevant lncRNAs that can take part in cell cycle regulation, cancer, chromatin modulation, and organism development. Our studies can serve as a comprehensive resource for future investigations on lncRNAs.
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| 11. |
- Subhash, Santhilal, 1987, et al.
(author)
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Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
- 2017
-
In: Journal of Visualized Experiments. - : MyJove Corporation. - 1940-087X. ; Genetics:124
-
Journal article (peer-reviewed)abstract
- The role of long noncoding RNAs (lncRNAs) in cancer is coming to the forefront due to growing interest in understanding their mechanistic functions during cancer development and progression. Despite this, the global epigenetic regulation of lncRNAs and repetitive sequences in cancer has not been well investigated, particularly in chronic lymphocytic leukemia (CLL). This study focuses on a unique approach: the immunoprecipitation-based capture of double-stranded, methylated DNA fragments using methyl-binding domain (MBD) proteins, followed by next-generation sequencing (MBD-seq). CLL patient samples belonging to two prognostic subgroups (5 IGVH mutated samples + 5 IGVH unmutated samples) were used in this study. Analysis revealed 5,800 hypermethylated and 12,570 hypomethylated CLL-specific differentially methylated genes (cllDMGs) compared to normal healthy controls. Importantly, these results identified several CLL-specific, differentially methylated lncRNAs, repetitive elements, and protein-coding genes with potential prognostic value. This work outlines a detailed protocol for an MBD-seq and bioinformatics pipeline developed for the comprehensive analysis of global methylation profiles in highly CpG-rich regions using CLL patient samples. Finally, a protein-coding gene and an lncRNA were validated using pyrosequencing, which is a highly quantitative method to analyze CpG methylation levels to further corroborate the findings from the MBD-seq protocol.
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| 12. |
- Subhash, Santhilal, 1987, et al.
(author)
-
GeneSCF: a real-time based functional enrichment tool with support for multiple organisms
- 2016
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In: BMC bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: High-throughput technologies such as ChIP-sequencing, RNA-sequencing, DNA sequencing and quantitative metabolomics generate a huge volume of data. Researchers often rely on functional enrichment tools to interpret the biological significance of the affected genes from these high-throughput studies. However, currently available functional enrichment tools need to be updated frequently to adapt to new entries from the functional database repositories. Hence there is a need for a simplified tool that can perform functional enrichment analysis by using updated information directly from the source databases such as KEGG, Reactome or Gene Ontology etc. Results: In this study, we focused on designing a command-line tool called GeneSCF (Gene Set Clustering based on Functional annotations), that can predict the functionally relevant biological information for a set of genes in a real-time updated manner. It is designed to handle information from more than 4000 organisms from freely available prominent functional databases like KEGG, Reactome and Gene Ontology. We successfully employed our tool on two of published datasets to predict the biologically relevant functional information. The core features of this tool were tested on Linux machines without the need for installation of more dependencies. Conclusions: GeneSCF is more reliable compared to other enrichment tools because of its ability to use reference functional databases in real-time to perform enrichment analysis. It is an easy-to-integrate tool with other pipelines available for downstream analysis of high-throughput data. More importantly, GeneSCF can run multiple gene lists simultaneously on different organisms thereby saving time for the users. Since the tool is designed to be ready-to-use, there is no need for any complex compilation and installation procedures.
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| 13. |
- Subhash, Santhilal, 1987, et al.
(author)
-
Global DNA methylation profiling reveals new insights into epigenetically deregulated protein coding and long noncoding RNAs in CLL.
- 2016
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In: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7083 .- 1868-7075. ; 8
-
Journal article (peer-reviewed)abstract
- Background: Methyl-CpG-binding domain protein enriched genome-wide sequencing (MBD-Seq) is a robust and powerful method for analyzing methylated CpG-rich regions with complete genome-wide coverage. In chronic lymphocytic leukemia (CLL), the role of CpG methylated regions associated with transcribed long noncoding RNAs (lncRNA) and repetitive genomic elements are poorly understood. Based on MBD-Seq, we characterized the global methylation profile of high CpG-rich regions in different CLL prognostic subgroups based on IGHV mutational status. Results: Our study identified 5800 hypermethylated and 12,570 hypomethylated CLL-specific differentially methylated genes (cllDMGs) compared to normal controls. From cllDMGs, 40 % of hypermethylated and 60 % of hypomethylated genes were mapped to noncoding RNAs. In addition, we found that the major repetitive elements such as short interspersed elements (SINE) and long interspersed elements (LINE) have a high percentage of cllDMRs (differentially methylated regions) in IGHV subgroups compared to normal controls. Finally, two novel lncRNAs (hypermethylated CRNDE and hypomethylated AC012065.7) were validated in an independent CLL sample cohort (48 samples) compared with 6 normal sorted B cell samples using quantitative pyrosequencing analysis. The methylation levels showed an inverse correlation to gene expression levels analyzed by real-time quantitative PCR. Notably, survival analysis revealed that hypermethylation of CRNDE and hypomethylation of AC012065.7 correlated with an inferior outcome. Conclusions: Thus, our comprehensive methylation analysis by MBD-Seq provided novel hyper and hypomethylated long noncoding RNAs, repetitive elements, along with protein coding genes as potential epigenetic-based CLL-signature genes involved in disease pathogenesis and prognosis.
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| 14. |
- Subhash, Santhilal, 1987, et al.
(author)
-
H3K4me2 and WDR5 enriched chromatin interacting long non-coding RNAs maintain transcriptionally competent chromatin at divergent transcriptional units
- 2018
-
In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 46:18, s. 9384-9400
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Journal article (peer-reviewed)abstract
- Recently lncRNAs have been implicated in the sub-compartmentalization of eukaryotic genome via genomic targeting of chromatin remodelers. To explore the function of lncRNAs in the maintenance of active chromatin, we characterized lncRNAs from the chromatin enriched with H3K4me2 and WDR5 using chromatin RNA immunoprecipitation (ChRIP). Significant portion of these enriched lncRNAs were arranged in antisense orientation with respect to their protein coding partners. Among these, 209 lncRNAs, commonly enriched in H3K4me2 and WDR5 chromatin fractions, were named as active chromatin associated lncRNAs (active lncCARs). Interestingly, 43% of these active lncCARs map to divergent transcription units. Divergent transcription (XH) units were overrepresented in the active lncCARs as compared to the inactive lncCARs. ChIP-seq analysis revealed that active XH transcription units are enriched with H3K4me2, H3K4me3 and WDR5. WDR5 depletion resulted in the loss of H3K4me3 but not H3K4me2 at the XH promoters. Active XH CARs interact with and recruit WDR5 to XH promoters, and their depletion leads to decrease in the expression of the corresponding protein coding genes and loss of H3K4me2, H3K4me3 and WDR5 at the active XH promoters. This study unravels a new facet of chromatin-based regulation at the divergent XH transcription units by this newly identified class of H3K4me2/WDR5 chromatin enriched lncRNAs.
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| 15. |
- Subhash, Santhilal, 1987, et al.
(author)
-
S-phase cancer associated lncRNAs
- 2018
-
In: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 17:23, s. 2517-2519
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Journal article (peer-reviewed)abstract
- Comment on: Ali MM, et al. Nature Communications 2018; 9:883.
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| 16. |
- Subhash, Santhilal, 1987, et al.
(author)
-
Sperm Originated Chromatin Imprints and LincRNAs in Organismal Development and Cancer
- 2020
-
In: iScience. - : Elsevier BV. - 2589-0042. ; 23:6
-
Journal article (peer-reviewed)abstract
- Importance of sperm-derived transcripts and chromatin imprints in organismal development is poorly investigated. Here using an integrative approach, we show that human sperm transcripts are equally important as oocyte. Sperm-specific and sperm-oocyte common transcripts carry distinct chromatin structures at their promoters correlating with corresponding transcript levels in sperm. Interestingly, sperm-specific H3K4me3 patterns at the lincRNA promoters are not maintained in the germ layers and somatic tissues. However, bivalent chromatin at the sperm-specific protein-coding gene promoters is maintained throughout the development. Sperm-specific transcripts reach their peak expression during zygotic genome activation, whereas sperm-oocyte common transcripts are present during early preimplantation development but decline at the onset of zygotic genome activation. Additionally, there is an inverse correlation between sperm-specific and sperm-oocyte lincRNAs throughout the development. Sperm-lincRNAs also show aberrant activation in tumors. Overall, our observations indicate that sperm transcripts carrying chromatin imprints may play an important role in human development and cancer.
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| 17. |
- Subhash, Santhilal, 1987, et al.
(author)
-
Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures : Long noncoding RNA molecular signatures in Cerebral Cavernous Malformations
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- Cerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.
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| 18. |
- Sukonina, Valentina, et al.
(author)
-
FOXK1 and FOXK2 regulate aerobic glycolysis.
- 2019
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 566, s. 279-283
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Journal article (peer-reviewed)abstract
- Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility1. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients2. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
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| 19. |
-
- 2019
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Journal article (peer-reviewed)
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