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Genome-wide analysis of JMJD1A and PPARγ binding in immortalized, differentiated preadipocytes derived from inguinal subcutaneous white adipose tissue.

ABSTRACT: In acute cold stress in mammals, JMJD1A, an H3K9 demethylase, up-regulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals also have another mechanism to cope with long-term cold stress by inducing the browning of subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation independent acute Ucp1 induction in BAT and demethylation dependent chronic Ucp1 expression in beige-scWAT provide complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namlely β-adrenergic receptor and PPARγ activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE107899 | GEO | 2018/02/16

REPOSITORIES: GEO

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RNA-sequence analysis of immortalized, differentiated preadipocytes derived from inguinal subcutaneous white adipose tissue.

Project description:In acute cold stress in mammals, JMJD1A, an H3K9 demethylase, up-regulates thermogenic gene expressions through β-adrenergic signaling in brown adipose tissue (BAT). Aside BAT-driven thermogenesis, mammals also have another mechanism to cope with long-term cold stress by inducing the browning of subcutaneous white adipose tissue (scWAT). Here, we show that this occurs through a two-step process that requires both β-adrenergic dependent phosphorylation of S265 and demethylation of H3K9me2 by JMJD1A. The histone demethylation independent acute Ucp1 induction in BAT and demethylation dependent chronic Ucp1 expression in beige-scWAT provide complementary molecular mechanisms to ensure an ordered transition between acute and chronic adaptation to cold stress. JMJD1A mediates two major signaling pathways, namlely β-adrenergic receptor and PPARγ activation, via PRDM16-PPARγ-P-JMJD1A complex for beige adipogenesis.

2018-02-16 | GSE107900 | GEO

RNA-sequence analysis of JMJD1A target genes in subcutanous white adipose tissue.

Project description:Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

2024-03-12 | GSE236733 | GEO

ATAC-sequence analysis of immortalized subcutanous white adipose tissue cells.

2024-03-12 | GSE236724 | GEO

Genome-wide analysis of JMJD1A binding in immortalized subcutaneous white adipose tissue cells.

Project description:Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis. Mechanistically, MYPT1-PP1β depletion resulted in JMJD1A-mediated H3K9 demethylation and activation of the Ucp1 enhancer/promoter regions. Interestingly, MYPT1-PP1β also dephosphorylates myosin light chain which regulates actomyosin tension-mediated activation of YAP/TAZ which directly stimulates Ucp1 gene expression. Preadipocyte specific Mypt1 deficiency increases cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice, confirming this regulatory mechanism in vivo. Thus, we have uncovered new regulatory cross-talk involved in beige adipogenesis that coordinates epigenetic regulation with direct activation of the mechano-sensitive YAP/TAZ transcriptional co-activators.

2022-09-01 | GSE202505 | GEO

RNA-seqence analysis of MYPT1 target genes in subcutaneous white adipoce tissue cells.

2022-09-01 | GSE202504 | GEO

β-adrenergic signaling-regulated MYPT1-PP1β phosphatase bridges chromatin states and actomyosin-tension-mediated YAP/TAZ transcriptional network for beige adipogenesis under cold stress

Project description:Protein kinase A phosphorylates proteins including histone H3 lysine 9 (H3K9) demethylase JMJD1A to facilitate beige adipogenesis upon β-adrenergic receptor (β-AR) activation, however, phosphatase(s) that antagonizes phosphorylation to inhibit beige adipogenesis is incompletely understood. Here we show that MYPT1-PP1β is a phosphatase that negatively regulates beige adipogenesis via dephosphorylation of pS265-JMJD1A and myosin regulatory light chain. Upon β-AR activation, MYPT1-PP1β is inhibited via T694 phosphorylation of MYPT1, facilitating phosphorylation of JMJD1A and beige adipogenesis under cold stress. Depletion of MYPT1-PP1β induces Ucp1 by orchestrating JMJD1A-mediated H3K9 demethylation and actomyosin-tension mediated YAP/TAZ activation. This induction of Ucp1 is abrogated in adipocytes expressing catalytically dead JMJD1A mutant, indicating that the coordinated epigenetic and transcriptional mechanisms are essential for beige adipogenesis. We also show that preadipocytes specific Mypt1 deficient mice exhibit higher cold tolerance with higher Ucp1 levels in subcutaneous white adipose tissues compared to control mice confirming its role at animal levels.

2022-09-26 | PXD031210 | JPOST Repository

Actomyosin-mediated tension orchestrates uncoupled respiration in adipose tissues

Project description:The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein-1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. Adrenergic signaling is viewed as a key regulator of thermogenesis and UCP1-expression in BAT, while also operating as a potent contractile stimulator in muscle. The muscle-like gene expression patterns of UCP1+ adipocytes have previously been utilized as tissue specific markers, but have not been attributed with any functional role. Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. We show that activation of actomyosin mechanics are critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Additionally, actomyosin-mediated elasticity regulates mechanosensitive transcriptional co-activators, YAP/TAZ, that facilitate the thermogenic capacity of adipocytes. These unappreciated signaling and mechanical mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.

2018-03-01 | GSE109829 | GEO

RNA-Sequencing of wild type and UCP1-null beige adipose tissue

Project description:Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the roles of classical brown and beige adipocytes, increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to analyze transcriptome of wild type and UCP1-null beige adipocyte to identify the UCP1-independent function.

2017-10-28 | E-MTAB-4085 | biostudies-arrayexpress

SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1  

Project description:Objective: Brown adipose tissue (BAT) is important for thermoregulation in many mammals. Uncoupling protein 1 (UCP1) is the critical regulator of thermogenesis in BAT. Here we aimed to investigate the deacetylation control of BAT and to investigate a possible functional connection between UCP1 and sirtuin 3 (SIRT3), the master mitochondrial deacetylase.   Methods: We carried out physiological, molecular and proteomic analyses of BAT from wild-type and Sirt3KO mice when BAT is activated. Mice were either cold exposed for 2 days or were injected with the β3-adrenergic agonist, CL316,243 (1mg/kg; i.p.). Mutagenesis studies were conducted in a cellular model to assess the impact of acetyaltion lysine sites on UCP1 function. Cardiac punctures were collected for Proteomic analysis of Acylcarnitines. Isolated mitochondria were used for functional analysis of OXPHOS.   Results: Our findings showed that SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria, without affecting UCP1 expression. Acetylome profiling of BAT mitochondria revealed that SIRT3 regulates acetylation status of many BAT mitochondrial proteins including UCP1 and crucial upstream proteins. Mutagenesis work in cells suggested that UCP1 activity was independent of direct SIRT3-regulated lysine acetylation. However, SIRT3 impacted BAT mitochondrial activities of acylcarnitine metabolism and specific electron transport chain complexes, CI and CII.  

2019-04-18 | PXD013056 | Pride

RNA-seq comparison of CD81 positive and negative cells in subcutaneous and visceral white fat and brown fat tissues in mouse

Project description:Subcutaneous white adipose tissue (scWAT) is known to undergo browning in response to cold exposure. The goal of this study is to identify elusive precursors found within scWAT that possess the ability to differentiate into beige adipocytes. A single cell transcriptomics experiment conducted by us identified the tetraspanin CD81 as a marker of adipose precursor cells (APC) that can convert to beige upon cold exposure. However, what distinguishes a CD81 positive APC from its CD81 negative counterpart in the same tissue, or in a different tissue remains unknown. Therefore, we applied bulk RNA-seq to sorted populations of Lineage negative Sca1+, CD81+/ CD81- cells from subcutaneous and visceral WAT, and brown adipose tissue to decipher the molecular underpinnings that render a CD81+ APC residing in scWAT, beige in response to browning.

2020-04-24 | E-MTAB-8435 | biostudies-arrayexpress

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