GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers

Clark, Erin; Wu, Feizhen; Chen, Yirui; Kang, Paco; Kaiser, Ursula B.; Fang, Rui; Shi, Yujiang Geno

doi:10.1016/j.celrep.2019.05.062

Cited by 26 publications

(13 citation statements)

References 53 publications

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“…Many nuclear receptors, including the glucocorticoid receptor, preferentially inhibit the H3K4me1-demethylase activity of KDM1A in A549, a lung adenocarcinoma cell line (Clark et al 2019). Similar inhibition was observed for KDM1A's interaction with POU5F1 at pluripotency enhancers in embryonal carcinoma cells (AlAbdi et al 2020).…”

Section: Discussionsupporting

confidence: 54%

KDM1A maintains genome-wide homeostasis of transcriptional enhancers

et al. 2021

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Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of monomethylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature of transcriptional enhancers. Lysine (K)-specific demethylase 1A (KDM1A, also known as LSD1), an H3K4me2/me1 demethylase, inactivates stem-cell enhancers during the differentiation of mouse embryonic stem cells (mESCs). However, its role in undifferentiated mESCs remains obscure. Here, we show that KDM1A actively maintains the optimal enhancer status in both undifferentiated and lineage-committed cells. KDM1A occupies a majority of enhancers in undifferentiated mESCs. KDM1A levels at enhancers exhibit clear positive correlations with its substrate H3K4me2, H3K27ac, and transcription at enhancers. In Kdm1a-deficient mESCs, a large fraction of these enhancers gains additional H3K4 methylation, which is accompanied by increases in H3K27 acetylation and increased expression of both enhancer RNAs (eRNAs) and target genes. In postmitotic neurons, loss of KDM1A leads to premature activation of neuronal activity-dependent enhancers and genes. Taken together, these results suggest that KDM1A is a versatile regulator of enhancers and acts as a rheostat to maintain optimal enhancer activity by counterbalancing H3K4 methylation at enhancers.

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Section: Discussionsupporting

confidence: 54%

KDM1A maintains genome-wide homeostasis of transcriptional enhancers

et al. 2021

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“…Recently, enhancer H3K4me2 was reported to inhibit GR binding in A549 cells ( Clark et al., 2019 ). We did not detect a correlation between H3K4me2 and GR occupancy at the Tsc22d3 and Dusp1 enhancers, but we did observe reduced transcriptional activation of these genes in our Setd1a mutant ( Figure 6 ; Figures S6 D, 6 G, 4 C and 5 B).…”

Section: Discussionmentioning

confidence: 99%

“…For any given cell type or condition, different pioneer factors, cellular signals, neighboring transcription factors, epigenetic environments, and coregulators may shape the GC response. In order to develop novel immunomodulatory therapies and to reduce the adverse effects of anti-inflammatory GC treatment, all of these different mechanisms may need to be considered (Sacta et al, 2018;Clark et al, 2019). Resource ll OPEN ACCESS douncing on ice.…”

Section: Discussionmentioning

confidence: 99%

“…Ligand-bound GR translocates to the nucleus to control target gene expression through GC response elements (GREs) or other binding sites present in promoters or enhancers. GR recruits transcriptional coregulators and enzymes, such as histone acetyltransferases (HATs) or histone deacetylases (HDACs), chromatin remodelers, p160 proteins, histone lysine methyltransferases (KMTs), and demethylases (KDMs), etc., to regulate transcription either positively or negatively ( Ito et al., 2000 ; Chen and Roeder, 2007 ; Chinenov et al., 2008 ; Uhlenhaut et al., 2013 ; Hua et al., 2016 ; Sacta et al., 2018 ; Clark et al., 2019 ). In fact, the details of how GR functions are inherently complex, and its presence in many cells and tissues makes selective pharmacological targeting difficult.…”

Section: Introductionmentioning

confidence: 99%

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The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers

et al. 2021

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Summary Glucocorticoids (GCs) are effective anti-inflammatory drugs; yet, their mechanisms of action are poorly understood. GCs bind to the glucocorticoid receptor (GR), a ligand-gated transcription factor controlling gene expression in numerous cell types. Here, we characterize GR’s protein interactome and find the SETD1A (SET domain containing 1A)/COMPASS (complex of proteins associated with Set1) histone H3 lysine 4 (H3K4) methyltransferase complex highly enriched in activated mouse macrophages. We show that SETD1A/COMPASS is recruited by GR to specific cis -regulatory elements, coinciding with H3K4 methylation dynamics at subsets of sites, upon treatment with lipopolysaccharide (LPS) and GCs. By chromatin immunoprecipitation sequencing (ChIP-seq) and RNA-seq, we identify subsets of GR target loci that display SETD1A occupancy, H3K4 mono-, di-, or tri-methylation patterns, and transcriptional changes. However, our data on methylation status and COMPASS recruitment suggest that SETD1A has additional transcriptional functions. Setd1a loss-of-function studies reveal that SETD1A/COMPASS is required for GR-controlled transcription of subsets of macrophage target genes. We demonstrate that the SETD1A/COMPASS complex cooperates with GR to mediate anti-inflammatory effects.

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“…GR binding sites can also work concordantly, with clusters of GREs mediating GR-dependent transcription [ 14 ]. GR binding can further control gene expression by modulating the epigenetic landscape around its target genes [ 15–17 ]. This epigenetic remodeling is likely a crucial component of GR-induced gene regulation, although more investigation is required to better decipher how loss of chromatin-modifying co-factors impacts expression of GR target genes.…”

Section: Glucocorticoid Steroids Act Through the Glucocorticoid Recepmentioning

confidence: 99%

Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy

Quattrocelli

Zelikovich

Salamone

et al. 2020

Journal of Neuromuscular Diseases

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Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences ranging from adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.

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GR and LSD1/KDM1A-Targeted Gene Activation Requires Selective H3K4me2 Demethylation at Enhancers

Cited by 26 publications

References 53 publications

KDM1A maintains genome-wide homeostasis of transcriptional enhancers

KDM1A maintains genome-wide homeostasis of transcriptional enhancers

The glucocorticoid receptor recruits the COMPASS complex to regulate inflammatory transcription at macrophage enhancers

Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy

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