# Control of gene silencing by long noncoding RNAs in trophoblast stem cells

> **NIH NIH F31** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $37,924

## Abstract

ABSTRACT
Long noncoding RNAs (lncRNAs) make up a large portion of mammalian transcriptomes and have essential
roles in diverse biological processes, including silencing of protein-coding genes during early development. In
the trophoblast, lncRNAs have been shown to have augmented silencing potency through their relationship with
highly conserved chromatin-modifying enzymes called Polycomb Repressive Complexes (PRCs). Specifically,
the lncRNAs Xist, Airn, and Kcnq1ot1 direct PRCs to separate genomic domains that each span millions of base
pairs, in which specific genes are silenced. Indeed, defective silencing by lncRNAs in the trophoblast leads
to inappropriate expression of genes that can be a major cause of infertility, whereby the preimplantation
embryo depends on the trophoblast for proper development. Despite the importance of the trophoblast in early
embryogenesis, the molecular mechanisms that sustain it, particularly through regulation of gene networks by
lncRNA silencing, are unknown. Recent work from our lab has shown that, in trophoblast stem cells (TSCs), the
genomic domains silenced by Xist, Airn, and Kcnq1ot1 harbor PRCs that are distributed non-uniformly, with
certain regions subject to greater levels of silencing than others. While the underlying features that establish this
non-uniformity are not fully known, we and others have proposed that chromatin-associated factors are at least
partly responsible. In our recent study, three-dimensional (3D) genome architecture and specific CpG island
(CGI) DNA elements appeared to be important contributors. Thus, using TSCs as an ex vivo model for the
trophoblast, I propose to investigate how chromatin conformation, contacts between chromatin and lncRNAs,
and sequence-specific transcription factors bound to CGIs cooperate to dictate both regional and long-distance
silencing in lncRNA-silenced domains. My studies will highlight specific factors that regulate epigenetic networks
that sustain the trophoblast. Furthermore, my work will provide new paradigms for gene regulation by lncRNAs,
whereby specific DNA-binding proteins control the intensity of silencing induced by lncRNAs on a region-by-
region basis. In turn, these data may provide new insights on how to treat birth defects or prevent the infertility
that results from altered dosage of lncRNA-silenced genes.
My long-term goal is to pursue a career in chromatin and epigenetics research as a principle investigator at a
major research institution. The training activities I propose are designed to prepare me for this goal, with the next
immediate step to obtain a postdoctoral fellowship in chromatin and epigenetics. To these ends, my research
plan will provide me with invaluable training in quantitative genomics and the skills needed to develop and
rigorously test hypotheses via computational and molecular cell biology. I have enlisted the help of a collaborator
and a co-sponsor whose computational expertise is complementary to that of my pr...

## Key facts

- **NIH application ID:** 10226855
- **Project number:** 5F31HD103370-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Aki Keean Braceros
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,924
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226855

## Citation

> US National Institutes of Health, RePORTER application 10226855, Control of gene silencing by long noncoding RNAs in trophoblast stem cells (5F31HD103370-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10226855. Licensed CC0.

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