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Epigenetic Regulation of Mitochondrial Homeostasis and Energy Metabolism

Award Number: R01DK121146
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Epigenetic Regulation of Mitochondrial Homeostasis and Energy Metabolism - PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD) contributes strongly to the development of insulin resistance, and the two mutually regulate each other in type 2 diabetes. In the liver of NAFLD and insulin resistance, hundreds to thousands of genes are either upregulated or downregulated. Epigenetic modifications such as histone methylation and acetylation modulate homochromatin or heterochromatin states to enhance or suppress gene expression in a context-dependent manner. However, significant knowledge gaps exist in mapping the epigenetic landscape and identifying the major epigenetic factors regulating the development of NAFLD and insulin resistance. In the current proposal, we take advantage of the newly developed CUT&TAG technology and create an epigenetic landscape of histone modifications, including H3K4me1 (poised marker), H3K4me2, and H3K27ac (active marker), and H3K9me2 (suppressive marker) in the liver of mouse and human NAFLD. A comprehensive analysis of the histone modification landscape identifies RE1 Silencing Transcription Factor (REST) as an epigenetic modulator that coordinates the activity of these histone markers. REST recruits histone deacetylases (HDAC1&2), which deacetylate H3K27ac, and lysine-specific demethylase 1 (LSD1), which demethylates H3K4me1 and H3K9me2, to regulate gene expression. Our preliminary data show that nuclear REST protein levels are increased in the liver of mouse and human NAFLD. Insulin and glucose treatment of cultured hepatocytes mimicking insulin resistance drives REST nuclear translocation. Knocking down REST using REST antisense oligonucleotides (ASO) in the liver of adult obese mice (REST-LKD) alleviates fatty liver and improves glucose and insulin tolerance. Hyperinsulinemic-euglycemic clamp studies show that REST knockdown in the liver increases glucose uptake in adipose tissue and muscle, indicating crosstalk between the liver and adipose tissue/muscle. These data show that hepatic REST is activated in insulin resistance, and the activated REST promotes the development of NAFLD and insulin resistance, forming a vicious cycle. Our central hypothesis is that REST is the key epigenetic factor orchestrating histone methylation and acetylation to regulate lipid and glucose metabolism in NAFLD and insulin resistance. We propose three aims to investigate what causes REST activation in NAFLD and insulin resistance, why the activated REST promotes NAFLD and insulin resistance, and how the activated REST induces systemic insulin resistance. Aim 1: To determine the mechanisms for the increased REST activity in the liver of NAFLD. Aim 2: To elucidate the mechanisms by which hepatic REST regulates lipid and glucose metabolism. Aim 3: To investigate the mechanisms for improved systemic insulin sensitivity in REST-LKD mice. Successful execution of the proposal will fill the knowledge gap by mapping the epigenetic landscape and identifying REST as a key epigenetic factor that reprograms metabolic gene profiles in NAFLD and insulin resistance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $493,084 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	6/23/2025	NON-COMPETING CONTINUATION	$493,084
2025	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $493,084

Issue Date FY: 2024 ( Subtotal = $469,243 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	6/27/2024	NON-COMPETING CONTINUATION	$469,243
														Subtotal = $469,243

Issue Date FY: 2023 ( Subtotal = $491,460 )
2023	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/29/2023	COMPETING CONTINUATION	$491,460
														Subtotal = $491,460

Issue Date FY: 2022 ( Subtotal = $392,500 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/24/2022	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2021 ( Subtotal = $392,500 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/13/2021	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2020 ( Subtotal = $392,500 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/11/2020	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2019 ( Subtotal = $390,416 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/20/2019	NEW	$390,416
														Subtotal = $390,416

Grand Total All Awards = $3,021,703

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Epigenetic Regulation of Mitochondrial Homeostasis and Energy Metabolism

Award Number: R01DK121146

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/21/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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