# Epigenetic regulation of lymphatic development

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $418,750

## Abstract

Project Summary/Abstract:
Lymphedema is the most common lymphatic anomaly and it is responsible for considerable morbidity, with no
current effective treatments. Improper drainage of extravasated protein-rich fluid from the tissues causes it to
accumulate, resulting in lymphedema. This condition frequently involves defective lymphatic valve
development, yet the epigenetic modifiers underlying lymphatic-valve morphogenesis remain unknown. Two
opposing classes of histone-modifying enzymes, histone acetyltransferases (HATs) and histone deacetylases
(HDACs) regulate the acetylation state of histones. Acetylation by HATs is generally associated with
transcriptional activation while HDAC-mediated deacetylation usually results in transcriptional repression.
HDACs lack intrinsic DNA-binding domains but modify epigenome in a signal-dependent manner via their
interactions with chromatin modifiers, transcription factors, and cofactors. Our findings suggest a novel
chromatin dependent, but deacetylase-independent role of Hdac3 in murine lymphatic valve development. We
find that Hdac3 functions as an essential flow-responsive epigenetic switch to establish a specific
transcriptional program for lymphatic valve development. Our data challenge long-held assumptions that
HDACs replace HATs to promote both histone deacetylation and repression of transcription. The goal of this
research program is to identify how Hdac3 establishes and maintains a specific transcriptional program for
lymphatic valve development. In addition, proposed studies will identify the mechanisms by which different
transcription factors, kinases, and phosphatases involved in signaling pathways regulate the chromatin
recruitment, phosphorylation, and function of Hdac3 within developing lymphatic vasculature. Despite intense
study in the area of epigenetics, very little is known about the role of epigenetic and chromatin modifiers in the
field of lymphatic development. The set of experiments outlined in this proposal have broad significance not
only for understanding how signaling pathways intersect with chromatin modifiers to regulate lymphatic valve
development, but also could be highly applicable to the entire field of congenital cardiovascular diseases.

## Key facts

- **NIH application ID:** 9922367
- **Project number:** 5R01HL141377-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Chinmay M Trivedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922367

## Citation

> US National Institutes of Health, RePORTER application 9922367, Epigenetic regulation of lymphatic development (5R01HL141377-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9922367. Licensed CC0.

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