GLP inhibits heterochromatin clustering and myogenic differentiation by repressing MeCP2

Choi, Myoung Hwan; Kala, Monica Palanichamy; Ow, Jin Rong; Rao, Vinay Kumar; Suriyamurthy, Sudha; Taneja, Reshma

doi:10.1093/jmcb/mjx038

Cited by 7 publications

(9 citation statements)

References 49 publications

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“…Otx2 binds to PNNs and enters the future PV + cell, where it triggers a genetic program for critical period plasticity (Beurdeley et al 2012;Prochiantz and Di Nardo 2015;Testa et al 2019) by upregulation of Gadd45b, a DNA demethylase that orchestrates the large-scale change in the transcriptomic landscape during the critical period, including clustering of MeCP2 in the nucleus (Apulei et al 2019), where it has been shown to directly bind to and methylate the Pvalb promoter region (Patrizi et al 2019). Interestingly, MeCP2 has recently been shown to be a direct target of Ehmt1 in non-neuronal cells (Choi et al 2018). Besides signalling by Otx2, another interesting candidate might be the signalling molecule BDNF, which is both important for PV + neuron maturation (Berghuis et al 2006;Huang et al 1999) and negatively regulated by EHMT1 (Benevento et al 2016).…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, we predict a delayed closing of the critical period in auditory and somatosensory cortex. Both the onset and the closing of the critical period require coordinated changes in gene expression in PV + neurons (Apulei et al 2019), which has been shown to require epigenetic remodeling such as by the DNA methylation reader MeCP2 (Krishnan et al 2015), which interestingly was recently shown to be a direct target of Ehmt1 in non-neuronal cells (Choi et al 2018). It is therefore conceivable that a loss of Ehmt1 would lead to a cellautonomous failure of epigenetic remodeling, resulting in an incomplete repression of previously expressed gene sets and thus a slowed transition into and out of the CP.…”

Section: Discussionmentioning

confidence: 99%

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EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas

et al. 2020

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Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a rare form of intellectual disability (ID) with strong autistic traits and sensory processing deficits. Proper development of inhibitory interneurons is crucial for sensory function. Here we report a timeline of Parvalbumin-positive (PV+) interneuron development in the three most important sensory cortical areas in the Ehmt1+/− mouse. We find a hitherto unreported delay of PV+ neuron maturation early in sensory development, with layer- and region-specific variability later in development. The delayed PV+ maturation is also reflected in a delayed maturation of GABAergic transmission in Ehmt1+/− auditory cortex, where we find a reduced GABA release probability specifically in putative PV+ synapses. Together with earlier reports of excitatory impairments in Ehmt1+/− neurons, we propose a shift in excitatory-inhibitory balance towards overexcitability in Ehmt1+/− sensory cortices as a consequence of early deficits in inhibitory maturation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas

et al. 2020

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“…During myogenesis, chromocenters consist of PCH domains fused together to form chromocenter clusters, which are easily recognized by an increase in size and reduction of the number of DAPI foci (19,20). Because ChRO1 was localized at the chromocenters, we were particularly interested in exploring whether ChRO1 might be involved in the reorganization of PCH domains during myogenesis.…”

Section: Resultsmentioning

confidence: 99%

“…To understand the dynamic reorganization of constitutive heterochromatin domains, we have analyzed myogenesis as a model system. Myogenesis is characterized by progressive ‘clustering’ of chromocenters that form a large heterochromatin compartment (19,20). Here, we describe the discovery of lncRNA ChRO1 that mediates constitutive heterochromatin reorganization during myogenesis.…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA ChRO1 facilitates ATRX/DAXX-dependent H3.3 deposition for transcription-associated heterochromatin reorganization

Park

Lee

Han

et al. 2018

Nucleic Acids Research

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Constitutive heterochromatin undergoes a dynamic clustering and spatial reorganization during myogenic differentiation. However the detailed mechanisms and its role in cell differentiation remain largely elusive. Here, we report the identification of a muscle-specific long non-coding RNA, ChRO1, involved in constitutive heterochromatin reorganization. ChRO1 is induced during terminal differentiation of myoblasts, and is specifically localized to the chromocenters in myotubes. ChRO1 is required for efficient cell differentiation, with global impacts on gene expression. It influences DNA methylation and chromatin compaction at peri/centromeric regions. Inhibition of ChRO1 leads to defects in the spatial fusion of chromocenters, and mislocalization of H4K20 trimethylation, Suv420H2, HP1, MeCP2 and cohesin. In particular, ChRO1 specifically associates with ATRX/DAXX/H3.3 complex at chromocenters to promote H3.3 incorporation and transcriptional induction of satellite repeats, which is essential for chromocenter clustering. Thus, our results unveil a mechanism involving a lncRNA that plays a role in large-scale heterochromatin reorganization and cell differentiation.

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“…Lysine methylation plays an important role in diverse cellular processes to regulate chromatin structures, genome stability, and fate determination of stem cells, etc (11)(12)(13)(14)(15)(16)(17)(18)(19). Many lysine methyltransferases harbor a Su(var)3-9-Enhancer of zeste-Trithorax (SET) domain, which is responsible for transferring a methyl group from S-adenosylmethionine to lysine residues.…”

Section: Introductionmentioning

confidence: 99%

Deletion of mouseSetd4promotes the recovery of hematopoietic failure

Feng

Yue

et al. 2019

Preprint

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Key points:• Deletion of Setd4 in adult mice improved the survival from hematopoietic failure.• Setd4 deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.• The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.Abstract: Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducing Setd4 deletion in adult mice, we found that loss of Setd4 improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of the Setd4 deficient HSC, but that Setd4 deficient HSC were actually more sensitive to radiation. However, the Setd4 deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis in Setd4 deficient mice. These findings not only revealed a previously unrecognized role of the Setd4 as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation. Authorship Contributions: XF and ZS: designed the experiments, performed data analysis, and drafted the initial versions of manuscript. XF: performed most of the experiments; HL, JL, and MS: performed and assisted with some of the experiments. HL, and JY: performed some of the early studies led to the construction of the mouse models; LD, and SD: provided resources for some experiments, computational analysis, and edited the manuscript. ZS: directed and oversaw the project, secured funding for the study, completed the final version of the manuscript. Conflict of Interest statement:The authors declare that there were no competing interests.

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GLP inhibits heterochromatin clustering and myogenic differentiation by repressing MeCP2

Cited by 7 publications

References 49 publications

EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas

EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas

Long non-coding RNA ChRO1 facilitates ATRX/DAXX-dependent H3.3 deposition for transcription-associated heterochromatin reorganization

Deletion of mouseSetd4promotes the recovery of hematopoietic failure

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