# MKRN3 imprinting, regulation, and action in the control of puberty

> **NIH NIH R00** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $248,920

## Abstract

ABSTRACT
Puberty and reproduction are controlled by the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is
active during the embryonic and neonatal stages of human life but then suppressed during childhood. The re-
activation of HPG axis results in puberty initiation. The precise mechanisms that regulate GnRH secretion to
constrain the HPG axis during infancy and childhood and subsequently trigger the initiation of puberty remain
elusive. The timing of puberty is associated with risks of subsequent disease and it is crucial to identify what
elicits puberty initiation. Complex interactions among genetic, nutritional, and environmental factors influence
pubertal initiation. We have recently identified loss-of-function mutations in MKRN3 in families with central
precocious puberty (CPP). MKRN3 is located on chromosome 15q and is maternally imprinted, expressed only
from the paternally inherited allele. The association of genetic mutations in MKRN3 with CPP is indisputable;
however, the possibility of imprinting abnormalities in MKRN3 as a cause of pubertal disorders has not been
explored. Epigenetic regulation of MKRN3 may be a link between environmental cues and pubertal timing. This
proposal will investigate the MKRN3 imprinting profile during pubertal development and determine if MKRN3
imprinting abnormalities are associated with pubertal disorders; and study the molecular mechanisms by which
MKRN3 regulates GnRH secretion. To this end, four distinct but complementary specific aims are proposed.
The mentored phase of the proposal will be carried out under Dr. Ursula Kaiser's supervision at Brigham and
Women's Hospital/Harvard Medical School. The aims of the K99 mentored phase are to: 1) Investigate the
MKRN3 methylation profile in different phases of human life and confirm the methylation pattern in mouse
tissues; and 2) Characterize the cellular and molecular mechanisms by which MKRN3 regulates GnRH
secretion in vitro. This training will provide expertise in DNA methylation studies, in hiPSC experiments, and in
RNA-Seq data analysis. The elucidation of the MKRN3 imprinting profile during normal pubertal development
and an understanding of the actions of MKRN3 in hypothalamic neurons will provide a strong base of
knowledge for the transition to the independent R00 phase of the award. Building on previous experience, the
aims of the R00 independent phase are to: 3) Investigate if abnormalities in MKRN3 imprinting are associated
with pubertal disorders; 4) Extend investigation of mechanisms of action of MKRN3 to in vivo mouse models.
This award includes a well-structured training program that includes course work and seminar learning
experiences. Completion of this project will lead to a better understanding of the molecular roles of MKRN3 in
the regulation of GnRH secretion and advance our fundamental knowledge of MKRN3 imprinting. The
successful completion of the aims of this proposal will bring new insights in the neuroendocrine regulati...

## Key facts

- **NIH application ID:** 10025263
- **Project number:** 5R00HD091381-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Ana Paula de Abreu e Silva Metzger
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,920
- **Award type:** 5
- **Project period:** 2019-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025263

## Citation

> US National Institutes of Health, RePORTER application 10025263, MKRN3 imprinting, regulation, and action in the control of puberty (5R00HD091381-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10025263. Licensed CC0.

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