Regulation of brown and beige adipogenesis by the histone reader DPF3

组蛋白读取器 DPF3 对棕色和米色脂肪生成的调节

基本信息

批准号：
9050089
负责人：
Suzanne Shapira
金额：
$ 4.31万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050089
关键词：
ATP phosphohydrolase Acute Adipocytes Adipose tissue Adrenergic Agents Affect Animals Binding Biology Body fat Brown Fat Burn injury Candidate Disease Gene Catabolism Cell Culture Techniques Cells Cessation of life ChIP-seq Chemicals Chromatin Remodeling Factor Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Complex Development Diet Disease Energy Metabolism Enhancers Epigenetic Process Fatty acid glycerol esters Gene Expression Genes Genetic Genetic Transcription Genome Genomic approach Goals Heating Histones Human Knockout Mice Lipids Mammals Measures Mediating Medical Membrane Potentials Metabolic Metabolic Diseases Metabolic stress Metabolism Mitochondria Modeling Morphology Mouse Strains Mus Norepinephrine Nuclear Receptors Nucleosomes Obesity Output Oxygen Consumption PHD Finger PPAR gamma Pathway interactions Phenotype Physiological Positioning Attribute Prevalence Proteins Public Health Reader Regulation Regulatory Element Respiration Role SMARCA4 gene System Testing Therapeutic Therapeutic Intervention Thermogenesis Tissues United States Weight Gain Zinc adipocyte differentiation adrenergic base chromatin remodeling combat combinatorial comorbidity density differential expression gain of function gene function gene therapy lipid biosynthesis loss of function mouse model mutant novel prevent programs public health relevance research study respiratory response subcutaneous therapeutic target transcription factor transcriptome sequencing treatment strategy

项目摘要

DESCRIPTION (provided by applicant): There is currently an urgent demand for new strategies to treat and prevent obesity and its associated diseases. A promising approach to combat these metabolic disorders is through enhancing the endogenous cellular mechanisms that can increase energy expenditure. Thermogenic brown and beige adipose tissue is specialized to burn energy through lipid catabolism to produce heat. In mice and humans, increasing the activity of these fat cells leads to increased energy expenditure and decreased body fat mass. Recently, a novel role for the histone reader Zinc And Double PHD Fingers 3 (DPF3) in brown and beige fat has emerged. DPF3 is a subunit in the mammalian BAF ATP-dependent chromatin remodeling complex. This complex, which acquires tissue-specific functions through combinatorial assembly of non-catalytic subunits, dynamically alters chromatin structure to facilitate access of transcriptional machinery to regulatory elements in the genome. Dpf3 expression is enriched in brown and beige adipocytes, and Dpf3 depletion in brown adipocytes blunts expression of key brown fat-specific genes that regulate energy expenditure. This proposal will test the hypothesis that DPF3 anchors the BAF chromatin-remodeling complex to transcriptionally activate thermogenic genes and support the increased respiratory capacity of brown and beige adipocytes. The first aim will elucidate the mechanisms by which DPF3 controls brown adipocyte differentiation through analysis of nucleosome positioning and recruitment of brown fat-specific transcription factors in the presence and absence of DPF3. Further, high-throughput genomic approaches followed by candidate-based analysis will be employed to identify and functionally characterize novel genes regulated by DPF3-directed BAF complexes. The second aim will determine the role of DPF3 in the physiological function of thermogenic adipocytes through quantitative assessment of mitochondrial metabolism and oxygen consumption in Dpf3 gain- and loss-of-function cell culture models. In addition, a Dpf3 knockout mouse strain will be analyzed to determine if null animals can activate brown and beige adipose tissue in response to metabolic stresses such as cold, β3-adrenergic stimulation, and high-fat diet. Together, the aims outlined in this proposal will reveal novel mechanisms by which DPF3 regulates the function of thermogenic adipocytes and define new epigenetic avenues that may be amenable to therapeutic intervention.

描述（由申请人提供）：目前迫切需要治疗和预防肥胖及其相关疾病的新策略，一种对抗这些代谢紊乱的有前景的方法是通过增强可增加能量消耗的内源性细胞机制。米色脂肪组织专门通过脂质分解代谢燃烧能量以产生热量，在小鼠和人类中，增加这些脂肪细胞的活性会导致能量消耗增加和体脂量减少。最近，组蛋白读取器锌和双的新作用。棕色和米色脂肪中的 PHD Fingers 3 (DPF3) 是哺乳动物 BAF ATP 依赖性染色质重塑复合物中的一个亚基，该复合物通过非催化亚基的组合组装获得组织特异性功能，动态改变染色质。促进转录机器接触调控元件的结构 Dpf3 表达在棕色和米色脂肪细胞中丰富，并且棕色脂肪细胞中 Dpf3 的缺失会减弱调节能量消耗的关键棕色脂肪特异性基因的表达，该提案将检验 DPF3 锚定 BAF 染色质重塑复合物以转录激活的假设。第一个目标是通过分析 DPF3 控制棕色脂肪细胞分化的机制。在存在和不存在 DPF3 的情况下棕色脂肪特异性转录因子的核小体定位和募集此外，将采用高通量基因组方法和基于候选的分析来识别和功能表征由 DPF3 引导的 BAF 复合物调节的新基因。第二个目标将通过评估 Dpf3 功能获得和丧失细胞培养模型中的线粒体代谢和氧消耗量来确定 DPF3 在生热脂肪细胞的生理功能中的作用。将分析 Dpf3 敲除小鼠品系，以确定无效动物是否可以激活棕色和米色脂肪组织以应对寒冷、β3 肾上腺素刺激和高脂肪饮食等代谢应激。总之，该提案中概述的目标将揭示新的目标。 DPF3 调节生热脂肪细胞功能的机制，并定义了可能适合治疗干预的新表观遗传途径。