Lsh/HELLS regulates self-renewal/proliferation of neural stem/progenitor cells

Han, Yingbo; Ren, Jianke; Lee, Eunice; Xu, Xiaoping; Yu, Weishi; Muegge, Kathrin

doi:10.1038/s41598-017-00804-6

Cited by 30 publications

(25 citation statements)

References 79 publications

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“…Also, hydroxymethylation changes are rare at promoters ( Figure 4B) and far from CpG islands ( Figure S4A Figure 4D). Functional analysis of differentially hydroxymethylated genes showed enrichment in GO term "tissue development", "tissue morphology" and "organismal development" (Figure S4C) highlighting again the global role of Lsh and the implication of (hydroxy)methylation in global development (41,56,57).…”

Section: Hmc Changes At the Genome-wide Level In Lsh Ko Mefsmentioning

confidence: 84%

The chromatin remodeler LSH controls genome-wide cytosine hydroxymethylation

Dieuleveult

Bizet

Colin

et al. 2020

Preprint

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TET proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), leading to a dynamic epigenetic state of DNA that can influence transcription. While TET proteins have been associated with either epigenetic repression or activation complexes, the overall understanding of the molecular mechanisms involved in TETmediated regulation of gene transcription still remains limited. Here, we show that TET proteins interact with lymphoid-specific helicase (LSH), a chromatin remodeling factor belonging to the SNF2 super family. Lsh knock-out leads to a significant reduction of 5-hydroxymethylation global level in mouse embryonic fibroblasts (MEFs) and in embryonic stem cells (ESC). Whole genome sequencing of 5hmC in wild-type versus Lsh knock-out MEFs and ESCs showed that in absence of Lsh, some regions of the genome gain 5hmC while others lose it, with not much effect on gene expression. We further show that 5hmC modifications upon Lsh loss is not a direct consequence of 5mC decrease, as differentially hydroxymethylated regions (DhMR) did not overlap with DMR (differentially methylated regions), underlying that these modifications occurred at different genomic loci. Altogether, our results suggest that LSH is a key regulator of 5hmC in both MEFs and ESC and that TET proteins rely on specific factors to establish genome-wide 5hmC patterns.

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Section: Hmc Changes At the Genome-wide Level In Lsh Ko Mefsmentioning

confidence: 84%

The chromatin remodeler LSH controls genome-wide cytosine hydroxymethylation

Dieuleveult

Bizet

Colin

et al. 2020

Preprint

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“…Our own studies, including this one, indicate that HELLS might be an attractive target for retinoblastoma therapeutics 10 . However, since HELLS is critical for the survival of mice and is required for normal tissue development, including the brain 17 , understanding the function of HELLS during retinal development is relevant if ocular delivery of HELLS inhibitors were to be considered as a therapeutic option for this retinal malignancy. Fortunately, unlike a previous report showing that HELLS mutant mice exhibit impaired neural progenitor cells selfrenewal and maintenance during development 17 , we show in this study that Hells depletion does not affect RPC (see figure on previous page) Fig.…”

Section: Discussionmentioning

confidence: 99%

“…HELLS plays an important role in normal development as HELLS knockout mice display perinatal lethality 15 . Furthermore, HELLS mutant mice exhibit signs of growth retardation, premature aging, and impaired neural stem/progenitor cells self-renewal and maintenance during development 16,17 . Thus, consideration of HELLS as a therapeutic target in the treatment of cancers requires careful consideration of the potential toxicities that could arise in tissues exposed to treatment.…”

Section: Introductionmentioning

confidence: 99%

Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression

Zocchi

Mehta

et al. 2020

Oncogenesis

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Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma.

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“…Although evidence has shown that certain bodymethylated genes gain non-CpG methylation in the absence of IBM1[19], methyl-CpG-binding protein 2(MeCP2) regulates non-CpG methylation in the mammalian brain[49], and domains rearranged methyltransferase (DRM) and chromomethylase 3(CMT3) maintain non-CpG methylation[50].However, the establishment of non-CpG methylation in cancer is poorly studied. LSH functions as an oncogene by promoting metastasis and genome instability and is involved in lipid metabolism in cancer cells and epigenetic regulates stem cell fate[27,50,51]. Our study found that LSH inhibits non-CpG methylation except for in repeat regions (CHH methylation).…”

mentioning

confidence: 80%

Identification of CpG methylation and non-CpG methylation is associate with Lymphocyte specific helicase

Lai¹,

Ouyang²,

Liu³

et al. 2020

Preprint

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Background : CpG methylation is crucial for normal cell development and differentiation in mammalian genomes, whereas non-CpG methylation presents in stem cells and appears to be enriched in pluripotent cell types. Lymphocyte-specific helicase (LSH) is critical for normal cell development as a regulator of CpG methylation, but whether there is potential link between LSH and non-CpG methylation remains unclear. Results: In this study, we using reduced representation bisulfite sequencing(RRBS), we found that LSH affected DNA methylation patterns in lung adenocarcinoma (LUAD) cells. We analyzed 12,239 differentially methylated regions (DMRs) for CpG methylation and 1605 DMRs for non-CpG methylation. LSH did not change CpG methylation at a global level, but partially change the methylation of CpG islands (CGIs). Interestingly, LSH reduced approximately 30% of CHH methylations at CGIs and consistently decreased CHG and CHH methylation patterns. However, LSH increased the CHH methylation level in satellite and simple-repeat region. The KEGG analysis showed LSH to be linked with a markedly enrichment in focal adhesion and the PI3K-Akt pathway. Further analysis indicated that LSH might epigenetically regulate the binding of transcription factors, including SP2, etc. Conclusions: These findings suggest that LSH have no remarkable influence on CpG methylation but it partially alter non-CpG methylation and repeat sequences in LUAD. LSH inhibits non-CpG methylation in cancer and may function as a regulator to promote tumorigenesis through inhibiting non-CpG methylation.

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Lsh/HELLS regulates self-renewal/proliferation of neural stem/progenitor cells

Cited by 30 publications

References 79 publications

The chromatin remodeler LSH controls genome-wide cytosine hydroxymethylation

The chromatin remodeler LSH controls genome-wide cytosine hydroxymethylation

Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression

Identification of CpG methylation and non-CpG methylation is associate with Lymphocyte specific helicase

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