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Nuclear Cell Biology and Methylation Codes of Ligand-Activated Enhancers Regulated by the Endocrine System

Award Number: R01DK144618
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: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Nuclear Cell Biology and Methylation Codes of Ligand-Activated Enhancers Regulated by the Endocrine System - ABSTRACT While significant advances have been made in elucidating enhancer function and the transcription of enhancer RNAs (eRNAs), a fundamental question remains: Do ligand- and signal-induced enhancer programs utilize distinct mechanisms for activation? Although CpG DNA methylation is recognized as a cornerstone of gene regulation, the mechanisms by which its state is selectively altered to enable cell-specific transcriptional responses in the endocrine system are not fully understood. This grant aims to deliver transformative insights into the unifying molecular mechanisms that underlie ligand/signal-dependent enhancer activation within the endocrine/paracrine system, both in vivo and in vitro. Specifically, we will: 1: Demonstrate that terminally oxidized DNA methylation marks - 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) - function as critical epigenetic switches that pre-mark enhancers, priming them for rapid and precise activation in response to intrinsic and extrinsic signals. We will show that these marks enable signal/ligand-activated transcription factors to recruit thymine DNA glycosylase (TDG), converting 5fC/5caC to abasic sites and stabilizing a topoisomerase 1-DNA covalent complex (TOP1cc) essential for enhancer activation. We will establish that this premarking mechanism constitutes a fundamental enhancer code governing the development of all endocrine cell types. We will validate this by identifying the pre-marked regulatory enhancer responsible for activating the Pit1 gene, in vivo. 2: Reveal the requirement of a novel subnuclear structure - the NEAT1-neospeckle for efficient recruitment of ligand- dependent transcription factors, such as the estrogen receptor (ERa). This process is mediated by intrinsically disordered regions of transcription factors and is critical for endocrine system function, with significant therapeutic implications.


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: 2026 ( Subtotal = $795,197 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/17/2026	NEW	$795,197
														Subtotal = $795,197

Grand Total All Awards = $795,197

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Nuclear Cell Biology and Methylation Codes of Ligand-Activated Enhancers Regulated by the Endocrine System

Award Number: R01DK144618

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: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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