LncRNA Mrhl orchestrates differentiation programs in mouse embryonic stem cells through chromatin mediated regulation

Pal, Debosree; Neha, C.V.; Bhaduri, Utsa; Zenia, Zenia; Dutta, Saurav K.; Chidambaram, Subbulakshmi; M, Rao

doi:10.1016/j.scr.2021.102250

Cited by 10 publications

(10 citation statements)

References 71 publications

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“…One interesting observation to be noticed was aberrant expression of 21 genes from WNT signaling pathway up on Hmrhl silencing, given the fact that in our previous study no link between the two was found, as translocation of β-catenin to nucleus was not observed under the same conditions in HeK293T cells ( 44 ). It will also be fascinating to mention here that mouse counter-part of Hmrhl, Mrhl was found to be inversely co-related with WNT-signaling in mouse spermatogonial cell line, GC1-Spg, while in the same species no regulation was observed between the two in mouse embryonic stem cells ( 42 , 43 ). This adds to the already evident fact that functional aspect of lncRNAs are highly cellular context driven and are rarely conserved.…”

Section: Discussionmentioning

confidence: 75%

“…Since, we had shown earlier that the mouse Mrhl RNA is nuclear restricted and has regulatory function at chromatin level ( 43 ), we were curious to examine the sub cellular localization of Hmrhl RNA in K562 cells. Results from biochemical fractionation studies indicate the presence of Hmrhl predominantly in the nuclear fraction which was in parallel with MALAT1, a well-known highly abundant nuclear enriched lncRNA in human (Figure 1C ) ( 31 ).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, a lncRNA might not regulate all the physically associated genomic region in every cells. Furthermore, examples from our own studies on lncRNA Mrhl, has shown that the gene targets of Mrhl lncRNA are quite different in the mouse spermatogonial cells and mouse embryonic stem (ES) cells ( 41 , 43 ) highlighting that the gene targets and consequent perturbation of gene expression will be cell type specific and context dependent even in the same species. Integrating whole transcriptome analysis and genome-wide chromatin association of Hmrhl, we systematically identified three genes ( ZIC1 , PDGRFβ and TP53 ) as potential regulatory targets of Hmrhl RNA.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the role of Mrhl in meiotic commitment of spermatogonial cells through regulation of SOX8 at the chromatin level has been documented ( 41 ). More recently, transcriptomics and genome-wide occupancy studies of Mrhl in mouse embryonic stem cells (mESCS) revealed its role as a chromatin regulator of cellular differentiation and development genes along with its probable importance in maintenance of stemness in mESCs ( 43 ).…”

Section: Introductionmentioning

confidence: 99%

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LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

et al. 2021

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Long non-coding RNA has emerged as a key regulator of myriad gene functions. One such lncRNA mrhl, reported by our group, was found to have important role in spermatogenesis and embryonic development in mouse. Recently, its human homolog, Hmrhl was shown to have differential expression in several type of cancers. In the present study, we further characterize molecular features of Hmrhl and gain insight into its functional role in leukemia by gene silencing and transcriptome-based studies. Results indicate its high expression in CML patient samples as well as in K562 cell line. Silencing experiments suggest role of Hmrhl in cell proliferation, migration & invasion. RNA-seq and ChiRP-seq data analysis further revealed its association with important biological processes, including perturbed expression of crucial TFs and cancer-related genes. Among them ZIC1, PDGRFβ and TP53 were identified as regulatory targets, with high possibility of triplex formation by Hmrhl at their promoter site. Further, overexpression of PDGRFβ in Hmrhl silenced cells resulted in rescue effect of cancer associated cellular phenotypes. In addition, we also found TAL-1 to be a potential regulator of Hmrhl expression in K562 cells. Thus, we hypothesize that Hmrhl lncRNA may play a significant role in the pathobiology of CML.

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Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

et al. 2021

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“…Due to the unavailability of required ChIP-seq datasets in spermatogonial cells, mouse embryonic stem cells and adult brain cortex were used as surrogate systems. Mrhl lncRNA is expressed in mESC while it isn’t expressed in the adult brain cortex (Pal et al, 2021). The inverse relationship between Mrhl and Sox8 expression in these two tissues was confirmed by analysing publicly available RNA-seq datasets (Fig 3B&C).…”

Section: Resultsmentioning

confidence: 99%

Regulation of Sox8 through lncRNA Mrhl mediated chromatin looping in mouse spermatogonia

Kayyar¹,

Ravikkumar²,

Bhaduri³

et al. 2021

Preprint

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Sox8 is a developmentally important transcription factor that plays an important role in sex maintenance and fertility of adult mice. In the B-type spermatogonial cells, Sox8 is regulated by the lncRNA Mrhl in a p68-dependant manner under the control of the Wnt signalling pathway. The downregulation of Mrhl leads to the meiotic commitment of the spermatogonial cells in a Sox8-dependant manner. While the molecular players involved in the regulation of transcription at the Sox8 promoter have been worked out, our current study points to the involvement of the architectural proteins, CTCF and cohesin, in mediating a chromatin loop. This loop brings the Sox8 promoter in contact with a silencer element present within the gene body in the presence of lncRNA Mrhl concomitant with transcriptional repression. Further, lncRNA Mrhl interacts with the Sox8 locus through the formation of a DNA:DNA:RNA triplex which is necessary for the recruitment of PRC2 to the locus. The downregulation of lncRNA Mrhl results in the promoter-silencer loop giving way to a promoter-enhancer loop. This active transcription associated chromatin loop is mediated by YY1 and brings the promoter in contact with the enhancer present downstream of the gene.

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Long noncoding RNA LINC01410 promotes tumorigenesis of osteosarcoma cells via miR‐497‐5p/HMGA2 axis

Gao

Zhang

et al. 2021

J Biochem & Molecular Tox

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LINC01410 is a tumor promoter that is upregulated in some cancer types, such as osteosarcoma (OS). Nonetheless, its role in OS and the underlying molecular mechanism have not been fully understood. Hence, we sought to elucidate it. We performed reverse‐transcription quantitative polymerase chain reaction for examining LINC01410, miR‐497‐5p and HMGA2 levels. Additionally, we carried out the cell counting kit‐8 and Transwell assays for detecting cell proliferation and invasion/migration. Bioinformatics predicted that there was a miR‐497‐5p binding site in LINC01410 or HMGA2; meanwhile, miR‐497‐5p was found to interact with HMGA2 and LINC01410 through dual‐luciferase reporter assay. LINC01410 and HMGA2 were high, and miR‐497‐5p showed low expression in OS tissues and cells. Cell function assay demonstrated that LINC01410 or HMGA2 knockdown or miR‐497‐5p overexpression obviously restrained OS proliferation, invasion, and migration. Oppositely, inhibiting miR‐497‐5p had the opposite effects. Functionally, miR‐497‐5p bound with LINC01410 3′‐untranslated region and HMGA2 was found to be the miR‐497‐5p target gene. Lastly, LINC01410 enhanced OS cell growth, invasion, and migration via decreasing miR‐497‐5p expression, whereas increasing that of HMGA2. We have demonstrated that LINC01410 promoted OS development partly by miR‐497‐5p/HMGA2 signal transduction pathway and this provides a reference for studying the mechanism of LINC01410 in OS.

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LncRNA Mrhl orchestrates differentiation programs in mouse embryonic stem cells through chromatin mediated regulation

Cited by 10 publications

References 71 publications

LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

Regulation of Sox8 through lncRNA Mrhl mediated chromatin looping in mouse spermatogonia

Long noncoding RNA LINC01410 promotes tumorigenesis of osteosarcoma cells via miR‐497‐5p/HMGA2 axis

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