LSD1—a pivotal epigenetic regulator of brown and beige fat differentiation and homeostasis

Lin, Jean Z.; Farmer, Stephen R.

doi:10.1101/gad.288720.116

Cited by 6 publications

(3 citation statements)

References 13 publications

(18 reference statements)

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“…There are several lines of evidence that LSD1 regulates BAT function and also mediates beige adipogenesis. The adipose tissue-specific LSD1-deficient mice produced by crossing an adiponectin-Cre line with an LSD1 floxed line shows reduced BAT thermogenesis [13,14]. The age-related transition of beige adipocytes to white [15,16] adipocytes is rescued by the adipocyte-specific expression of LSD1 through maintaining the expression of PPARα [15].…”

Section: Regulations Of Beige Adipogenesis By Histone Methyl-modifyinmentioning

confidence: 99%

Histone demethylases regulate adipocyte thermogenesis

Inagaki

2018

Diabetol Int

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Adipocytes play a pivotal role in the regulation of energy metabolism. While white adipocyte stores energy, brown adipocyte dissipates energy by producing heat. In addition, another type of heat-producing adipocyte, beige adipocyte, emerges in white adipose tissue in response to chronic coldness. This phenotypic adaptation to the cold environment is considered to be attributed to the epigenetic modifications. Histone methylation is a chemically stable epigenetic modification and thus a proper mechanism for long-lasting cellular memory. Several histone methyl-modifying enzymes such as EHMT1, JMJD1A, JMJD3, and LSD1 are reported to be involved in the beige adipose cell fate determination. Among these, a histone demethylase JMJD1A senses cold environment by being phosphorylated at S265 in response to β-adrenergic receptor stimulation. Phosphorylated JMJD1A regulates both acute and cold thermogenesis. Under acute coldness, phosphorylated JMJD1A forms a complex with chromatin remodeler SWI/SNF and DNA-bound PPARγ, which recruits JMJD1A to the target genomic regions in brown adipocyte. This complex formation, in turn, induces the expression of target genes by bringing the enhancer and the promoter into close proximity. During chronic coldness, phosphorylated JMJD1A regulates beige adipogenesis through a two-step mechanism. In the first step, phosphorylated JMJD1A is recruited to the regulatory regions of target genes by forming a complex with PRDM16, PGC1α, and DNA-bound PPARγ. In the second step, JMJD1A demethylates histone H3K9me2 and induces stable expression of beige-selective genes. The phenotypic analyses of Jmjd1a-null mice and non-phosphorylated mutant S265A Jmjd1a knock-in mice indicate that JMJD1A is a potential therapeutic target for the treatment of obesity-related diseases including metabolic syndrome and type 2 diabetes.

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Section: Regulations Of Beige Adipogenesis By Histone Methyl-modifyinmentioning

confidence: 99%

Histone demethylases regulate adipocyte thermogenesis

Inagaki

2018

Diabetol Int

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“…LSD1 uses FAD formed from ATP and riboflavin (vitamin B2) in mitochondria as a cofactor to demethylate mono- and di-methylated H3K4 and H3K9 ( 72 , 73 ). Although LSD1 demethylase activity appears to control the metabolism in favor of de novo fatty acid synthesis over gluconeogenesis in hepatocyte and brown adipose tissue thermogenic activity, a direct link between nutritional status and LSD1 activity still needs to be established ( 74 – 78 ). For instance, recent works demonstrate that livers from mouse fed with folate-deficient diet present an increased dimethyl-H3K4 and decreased LSD1 activity ( 79 ).…”

Section: Flavin Adenine Dinucleotide (Fad) and Histone Demethylasesmentioning

confidence: 99%

Cofactors As Metabolic Sensors Driving Cell Adaptation in Physiology and Disease

et al. 2017

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Chromatin architectures and epigenetic fingerprint regulation are fundamental for genetically determined biological processes. Chemical modifications of the chromatin template sensitize the genome to intracellular metabolism changes to set up diverse functional adaptive states. Accumulated evidence suggests that the action of epigenetic modifiers is sensitive to changes in dietary components and cellular metabolism intermediates, linking nutrition and energy metabolism to gene expression plasticity. Histone posttranslational modifications create a code that acts as a metabolic sensor, translating changes in metabolism into stable gene expression patterns. These observations support the notion that epigenetic reprograming-linked energy input is connected to the etiology of metabolic diseases and cancer. In the present review, we introduce the role of epigenetic cofactors and their relation with nutrient intake and we question the links between epigenetic regulation and the development of metabolic diseases.

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“…Nevertheless, both the normal functions of LSD1 in the intestine and its potential role in intestinal cancers are poorly understood. LSD1 has been directly implicated as a regulator of neuronal and myeloid differentiation, brown adiposities, and muscle cells (Laurent et al, 2015) (Maiques-Diaz et al, 2018) (Lin and Farmer, 2016) (Tosic et al, 2018). Furthermore, recent studies have begun to connect LSD1 with the regulation of intestinal secretory lineages.…”

Section: Introductionmentioning

confidence: 99%

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

Miller

Policastro

Sriramkumar

et al. 2020

Preprint

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Despite the connection to distinct mucus-containing colorectal cancer (CRC) histological subtypes, the role of secretory cells, including goblet and enteroendocrine (EEC) cells, in CRC progression has been underexplored. Analysis of TCGA and single cell RNA sequencing data demonstrates that multiple secretory progenitor populations are enriched in BRAF-mutant CRC patient tumors and cell lines. Enrichment of EEC progenitors in BRAF-mutant CRC is maintained by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of EECs. Mechanistically, secretory cells and the factors they secrete, such as Trefoil factor 3, are shown to promote colony formation and activation of cell survival pathways in the entire cell population. We further identify LSD1 as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss reduces tumor growth and metastasis. This work establishes EEC progenitors, in addition to goblet cells, as targetable populations in BRAF-mutant CRC and identifies LSD1 as a therapeutic target in secretory lineage-containing CRC.

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LSD1—a pivotal epigenetic regulator of brown and beige fat differentiation and homeostasis

Cited by 6 publications

References 13 publications

Histone demethylases regulate adipocyte thermogenesis

Histone demethylases regulate adipocyte thermogenesis

Cofactors As Metabolic Sensors Driving Cell Adaptation in Physiology and Disease

LSD1 promotes secretory cell specification to driveBRAFmutant colorectal cancer

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