The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease

Aubert, Yann; Egolf, Shaun; Capell, Brian C.

doi:10.1016/j.tig.2019.06.004

Cited by 31 publications

(22 citation statements)

References 96 publications

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“…Increasing spatiotemporal resolution of the molecular study is an important future direction. Second, histone modifying enzymes, including KDM5C, can exert non-enzymatic function 11,39 . Although it has not been reported, there might be a non-histone substrate for KMT2A and KDM5C, as shown in other histone modifying enzymes 12 .…”

Section: Discussionmentioning

confidence: 99%

“…These human conditions can be collectively referred to as brain H3K4 methylopathies and point to non-redundant yet poorly understood roles of these genes controlling this single post-translational modification for faithful brain development. Of note, some of these enzymes can have non-enzymatic scaffolding function 11 as well as non-histone substrates 12 ; therefore, these disorders may potentially involve mechanism outside histone H3K4 methylation.…”

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confidence: 99%

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Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

et al. 2020

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Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

et al. 2020

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“…Enhancer priming by H3K4me1 has been suggested to precede and facilitate enhancer activation 17,19,60,71 . However, direct evidence supporting the functional relevance of H3K4me1 is scarce, partly due to the difficulties to separate the enzymatic and non-enzymatic functions of histone methyltransferases 75 . Recently, this limitation was overcome by establishing Mll3/4 catalytic mutant ESC lines ( i.e.…”

Section: Discussionmentioning

confidence: 99%

Enhancer-associated H3K4 methylation safeguards in vitro germline competence

Bleckwehl

Crispatzu

Schaaf

et al. 2020

Preprint

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SUMMARYGermline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast reactivate a naïve pluripotency expression program and differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain largely unknown.Here we show that early germline genes that are active in the naïve pluripotent state become homogeneously dismantled in germline competent epiblast cells. In contrast, the enhancers controlling the expression of major PGC genes transiently and heterogeneously acquire a primed state characterized by intermediate DNA methylation, chromatin accessibility, and H3K4me1. This primed enhancer state is lost, together with germline competence, as epiblast cells develop further. Importantly, we demonstrate that priming by H3K4me1/2 enables the robust activation of PGC enhancers and is required for germline competence and specification. Our work suggests that H3K4me1/2 is directly involved in enhancer priming and the acquisition of competence.

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“…Since the dysfunction of histone-modifying enzymes (HME) has been linked to human cancer initiation and progression, the CLL research community has placed significant emphasis on investigating HME. While initial studies have focused on canonical HME functions (catalyzing histone modifications), a few recent studies have explored the nonenzymatic roles of HME in transcriptional regulation [45].…”

Section: Histone-modifying Enzymes: Targets For Therapymentioning

confidence: 99%

“…Although all aforementioned studies have indicated an important role of HME in CLL, there is a therapeutic potential in light of combinatorial therapies (i.e., BCR signaling inhibitors and HME inhibitors) which is not yet systematically explored. Given the significant number and diversity of HME, together with canonical and recently emerging non-canonical functions [45], it is now evident that in-depth understanding of HMEspecific functions is perquisite for designing a successful epigenetically relevant combinatorial therapy.…”

Section: Histone-modifying Enzymes: Targets For Therapymentioning

confidence: 99%

Advances in Epigenetics and Epigenomics in Chronic Lymphocytic Leukemia

Xanthopoulos

Kostareli

2019

Curr Genet Med Rep

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Purpose of Review The development and progression of chronic lymphocytic leukemia (CLL), a highly heterogenous B cell malignancy, are influenced by both genetic and environmental factors. Environmental factors, including pharmacological interventions, can affect the epigenetic landscape of CLL and thereby determine the CLL phenotype, clonal evolution, and clinical outcome. In this review, we critically present the latest advances in the field of CLL epigenomics/epigenetics in order to provide a systematic overview of to-date achievements and highlight the potential of epigenomics approaches in light of novel treatment therapies. Recent Findings Recent technological advances have enabled broad and precise mapping of the CLL epigenome. The identification of CLL-specific DNA methylation patterns has allowed for accurate CLL subtype definition, a better understanding of clonal origin and evolution, and the discovery of reliable biomarkers. More recently, studies have started to unravel the prognostic, predictive, and therapeutic potential of mapping chromatin dynamics and histone modifications in CLL. Finally, analysis of non-coding RNA expression has indicated their contribution to disease pathogenesis and helped to define prognostic subsets in CLL. Summary Overall, the potential of CLL epigenomics for predicting treatment response and resistance is mounting, especially with the advent of novel targeted CLL therapies.

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The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease

Cited by 31 publications

References 96 publications

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

Enhancer-associated H3K4 methylation safeguards in vitro germline competence

Advances in Epigenetics and Epigenomics in Chronic Lymphocytic Leukemia

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