The SNF2 family ATPase LSH promotes cell-autonomous<i>de novo</i>DNA methylation in somatic cells

Termanis, Ausma; Torrea, Natalia; Culley, Jayne; Kerr, Alastair; Ramsahoye, Bernard; Stancheva, Irina

doi:10.1093/nar/gkw424

Cited by 23 publications

(17 citation statements)

References 42 publications

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“…HELLS has been implicated in the establishment of genome-wide methylation patterns and chromatin repression (Termanis et al, 2016;Yu et al, 2014). HELLS ATPase domain is required for these functions (Burrage et al, 2012;Ren et al, 2015;Termanis et al, 2016), and ATP is necessary for nucleosome remodeling in vitro (Jenness et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce

Dlamini

Ananda

et al. 2019

Preprint

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Chromatin barriers prevent spurious interactions between regulatory elements and DNAbinding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hotspots and provide access for the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited to hotspots by PRDM9, and is necessary for both histone modifications and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

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Section: Discussionmentioning

confidence: 99%

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce

Dlamini

Ananda

et al. 2019

Preprint

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“…Consistently, DNMT3 enzymes form complexes with various chromatin remodelers, including SMARCA4 ( 150 ), CHD4 ( 151 ), hSNF2 ( 152 ) and HELLS ( 153 , 154 ). Notably, the interaction with HELLS is essential for de novo DNA methylation ( 155 , 156 ). In line with this model, remodeling activity promotes the methylation of nucleosomal DNA ( 148 ).…”

Section: Structure Mechanism and Regulation Of Dnmt3 Enzymesmentioning

confidence: 99%

Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm

2016

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In mammals, DNA methylation is introduced by the DNMT1, DNMT3A and DNMT3B methyltransferases, which are all large multi-domain proteins containing a catalytic C-terminal domain and an N-terminal part with regulatory functions. Recently, two novel regulatory principles of DNMTs were uncovered. It was shown that their catalytic activity is under allosteric control of N-terminal domains with autoinhibitory function, the RFT and CXXC domains in DNMT1 and the ADD domain in DNMT3. Moreover, targeting and activity of DNMTs were found to be regulated in a concerted manner by interactors and posttranslational modifications (PTMs). In this review, we describe the structures and domain composition of the DNMT1 and DNMT3 enzymes, their DNA binding, catalytic mechanism, multimerization and the processes controlling their stability in cells with a focus on their regulation and chromatin targeting by PTMs, interactors and chromatin modifications. We propose that the allosteric regulation of DNMTs by autoinhibitory domains acts as a general switch for the modulation of the function of DNMTs, providing numerous possibilities for interacting proteins, nucleic acids or PTMs to regulate DNMT activity and targeting. The combined regulation of DNMT targeting and catalytic activity contributes to the precise spatiotemporal control of DNMT function and genome methylation in cells.

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“…17,18 Mutations of human Lsh (HELLS) cause ICF (immunodeficiency, centromeric instability, facial anomalies) syndrome, a severe human disease that is frequently lethal at an early age. 19 Lsh has been reported to regulate DNA de novo methylation [20][21][22] and nucleosome density at repeat sequences during mouse development and cellular differentiation. 23 It is also involved in the regulation of histone modifications.…”

Section: Introductionmentioning

confidence: 99%

Tethering of Lsh at the Oct4 locus promotes gene repression associated with epigenetic changes

et al. 2018

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Lsh is a chromatin remodeling factor that regulates DNA methylation and chromatin function in mammals. The dynamics of these chromatin changes and whether they are directly controlled by Lsh remain unclear. To understand the molecular mechanisms of Lsh chromatin controlled regulation of gene expression, we established a tethering system that recruits a Gal4-Lsh fusion protein to an engineered Oct4 locus through Gal4 binding sites in murine embryonic stem (ES) cells. We examined the molecular epigenetic events induced by Lsh binding including: histone modification, DNA methylation and chromatin accessibility to determine nucleosome occupancy before and after embryonic stem cell differentiation. Our results indicate that Lsh assists gene repression upon binding to the Oct4 promoter region. Furthermore, we detected less chromatin accessibility and reduced active histone modifications at the tethered site in undifferentiated ES, while GFP reporter gene expression and DNA methylation patterns remained unchanged at this stage. Upon differentiation, association of Lsh promotes transcriptional repression of the reporter gene accompanied by the increase of repressive histone marks and a gain of DNA methylation at distal and proximal Oct4 enhancer sites. Taken together, this approach allowed us to examine Lsh mediated epigenetic regulation as a dynamic process and revealed chromatin accessibility changes as the primary consequence of Lsh function.

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The SNF2 family ATPase LSH promotes cell-autonomousde novoDNA methylation in somatic cells

Cited by 23 publications

References 42 publications

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm

Tethering of Lsh at the Oct4 locus promotes gene repression associated with epigenetic changes

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