# Genomic and Translational Approaches to Neuroendocrine Switching Events

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $664,012

## Abstract

During the past five year period, this Merit Award has permitted us to focus on molecular “epigenomic”
strategies that combinatorially regulate programs of gene transcription. These include identifying new
epigenetic regulators; defining signatures of active enhancers; and providing evidence that enhancers
mediating actions of liganded nuclear receptors are themselves regulated transcription units, transcribing
functionally important eRNAs. We have also identified new histone modifications and elucidated their
biological functions, and contributed to the growing evidence for dynamic three-dimensional
interaction/reorganization of specific genomic regions. Finally, we have provided initial evidence that
lncRNAs could exert their biological functions based on their actions to allosterically modify functions of
RNA-binding proteins, and of retinoic acid receptor regulation of Pol III-dependent Alu repeat transcription
units and their roles in biological processes. Specific contributions include: elucidating the roles of PHF8,
PHF2 and SMYD5 in transcriptional regulation; identifying roles of a tissue-specific splice variant of LSD1;
finding a novel tyrosine phosphorylation of H2A and; demonstrating the role of JMJD6 demethylase as a
regulator of pause-release by actions on specific enhancers. We characterized the E2-regulated enhancer
program and the ligand-dependent increase in eRNA transcription as a signature of functional enhancers.
We identified the recruitment of the MegaTrans complex and Condensins I and II to these functional
enhancers. Using Pit1 as a model, we also demonstrated the requirement for Pit1-dependent enhancer
interactions with the Matrin3-rich network for effective activation of homeodomain-dependent transcriptional
programs in the endocrine system. We propose to continue our work in this extension by exploring the roles
of nuclear receptors in regulating negative, as well as positive, enhancer-dependent transcriptional
programs, defining the roles of JMJD6 in these programs, and roles of modified long-distance interactions in
dictating the chromosomal alterations underlying regulated transcriptional response. We will use genetic
approaches to elucidate the mechanisms of super-enhancer regulation of endocrine developmental
programs in the endocrine system.
RELEVANCE (See instructions):
Under this MERIT Award, we have contributed to understanding the enhancer-dependent strategies
regulating broad gene transcriptional programs. We will continue and extend these studies in the MERIT
Extension period by investigating global enhancer interaction networks; mechanisms of negative as well as
positive gene transcriptional regulatory programs; and elucidating developmental roles of component
enhancers in superenhancers in the endocrine system.

## Key facts

- **NIH application ID:** 9830636
- **Project number:** 5R37DK039949-38
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** MICHAEL G ROSENFELD
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $664,012
- **Award type:** 5
- **Project period:** 2015-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830636

## Citation

> US National Institutes of Health, RePORTER application 9830636, Genomic and Translational Approaches to Neuroendocrine Switching Events (5R37DK039949-38). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830636. Licensed CC0.

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