# Wyoming IDeA Networks for Biomedical Research Excellence Phase 4

> **NIH NIH P20** · UNIVERSITY OF WYOMING · 2020 · $251,694

## Abstract

Peptidylarginine deiminase (PAD) enzymes epigenetically regulate gene expression in pituitary
lactotrope cells; yet, the physiological consequences of this on lactotrope function during
pregnancy and lactation are unknown. This gap in knowledge is important because lactotrope
remodeling during pregnancy is absolutely required to maximize prolactin synthesis, initiate
lactation, and stimulate breastmilk production. This is a highly relevant medical question
because breastfeeding has profound health benefits for both the mother and infant. Our long-
term goal is to understand hormone mediated epigenetic control of lactation at the molecular
level. The objective of this proposal is to show that PAD catalyzed histone citrullination is a
novel regulator of miRNA biogenesis that mediates 17β-estradiol (E2) induced lactotrope
population changes during pregnancy. Our data demonstrate that PAD expression is highest in
lactotropes from late pregnant mice and that these enzymes suppress expression of a
riboprotein termed DGCR8 microprocessor complex subunit (DGCR8) which is critical for
miRNA biogenesis. We propose a model in which E2 stimulates PAD expression, and then
histone citrullination suppresses miRNA biogenesis. With decreased miRNAs, mRNAs encoding
important proliferative, growth factor and gap junction proteins increase to drive lactotrope
remodeling during pregnancy. Our central hypothesis is that E2 increases expression of PAD
enzymes which then citrullinate histones to suppress miRNA processing in lactotropes during
pregnancy. The central hypothesis will be tested with the following specific aims: (1) Determine
the mechanism by which E2 regulates PAD expression and histone citrullination in lactotropes;
(2) Determine the role of DGCR8 in miRNA biogenesis in lactotropes. The work is significant
because it is an important step to characterize a completely novel, unexplored mechanism that is
essential for lactotrope population changes during pregnancy and ultimately lactation. The
proposed research is innovative because investigating histone citrullination induced miRNA
biogenesis represents a new and substantial departure from current studies in the field.

## Key facts

- **NIH application ID:** 10153115
- **Project number:** 3P20GM103432-19S1
- **Recipient organization:** UNIVERSITY OF WYOMING
- **Principal Investigator:** Robert Scott Seville
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $251,694
- **Award type:** 3
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153115

## Citation

> US National Institutes of Health, RePORTER application 10153115, Wyoming IDeA Networks for Biomedical Research Excellence Phase 4 (3P20GM103432-19S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10153115. Licensed CC0.

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