# Mechanisms for histone segregation at DNA replication forks and implications for epigenetic inheritance.

> **NIH NIH K99** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $99,999

## Abstract

Epigenetic information encoded in chromatin is responsible for sustaining transcriptional programs that
determine cell identity and regulate differentiation. In every mitotic cell division, this epigenetic information
must be faithfully transmitted to daughter cells to preserve specific transcriptional landscapes. Failure in this
process compromises the maintenance of cell identity and can lead to tumorigenesis. Histone
posttranslational modifications control the interactions between DNA and other proteins, like transcription
factors, and are therefore considered epigenetic marks. However, how these histone modifications, present
at parental nucleosomes, are transferred to both leading and lagging strands during DNA replication remains
largely unknown. Using the novel method eSPAN to determine strand-specific protein enrichment at
replication forks, we have recently shown how two non-essential subunits of leading strand DNA polymerase
𝝴 and the Mcm2-Ctf4-Pol α axis mediate parental histone transfer to leading and lagging strands, respectively.
These important findings indicate that a symmetric inheritance of epigenetic information between daughter
cells requires the action of several different factors. However, mutations at these known factors impacting
parental histone transfer have a minor effect on cell viability. Therefore, I hypothesize that a complex network
of proteins yet to be discovered regulates this process. This project will focus on the identification and
characterization of all those factors involved in the segregation of parental histones to nascent DNA strands
using a combination of genetic, biochemical and genome approaches. Our first aim will be to determine how
the conserved master regulator of replication PCNA functions in deposition of parental nucleosomes to
lagging strands (Aim 1). Our second aim is to identify and characterize additional factors playing a role in the
transmission of epigenetic information to daughter DNA strands using a combination of candidate and
genome wide screen approaches (Aim 2). Moreover, we will adapt the eSPAN method to investigate the re-
establishment of heterochromatin on newly synthesized DNA strands to delve further into the relationship
between asymmetric parental nucleosome segregation and loss of transcriptional silencing. Taken together,
this project will shed light into the underlying mechanisms of epigenetic inheritance, a critical but poorly
understood process involved in several diseases like cancer. Aim 1 will be started and completed during the
K99 phase under the mentorship of Dr. Zhiguo Zhang, a leader in the field of histone epigenetics, at Columbia
University, an outstanding research institution. Aim 2 will start at the end of K99 phase but will continue during
the R00 independent phase. The funds and support from this award will allow me to focus on my research
while giving me the opportunity to learn about laboratory management, technology development, and data
analysis, cri...

## Key facts

- **NIH application ID:** 10019581
- **Project number:** 5K99GM134180-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Albert Serra Cardona
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,999
- **Award type:** 5
- **Project period:** 2019-09-17 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019581

## Citation

> US National Institutes of Health, RePORTER application 10019581, Mechanisms for histone segregation at DNA replication forks and implications for epigenetic inheritance. (5K99GM134180-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10019581. Licensed CC0.

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