# Mechanism of Epigenetic Inheritance

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $846,662

## Abstract

In eukaryotic cells, genomic DNA is packaged into chromatin that encodes epigenetic information and maintain
genome integrity. Chromatin is further organized into distinct functional domains, such as heterochromatin and
euchromatin, that contain different post-translational histone modifications (PTM). How different chromatin states
are inherited during S phase of the cell cycle is one of the most challenging questions in the chromatin and
epigenetic fields. The “first” step in this complex process is the assembly of replicated DNA into nucleosomes
using both parental and newly-synthesized histones in a process that is tightly coupled to ongoing DNA synthesis.
We have been studying how nucleosomes are formed following DNA replication and have made multiple major
contributions to this process. However, how parental histone (H3-H4)2 tetramers, the primary carrier of epigenetic
modifications, are transferred to replicating DNA is still poorly understood, which hinders our understanding of
the transmission of epigenetic information into daughter cells. The major challenge to understanding parental
histone (H3-H4)2 assembly is a lack of methods to track this process. We have developed the eSPAN
(enrichment and Sequencing Protein- Associated Nascent DNA) method that can discern whether a protein
binds to leading or lagging strands of DNA replication forks in both yeast and mouse embryonic stem (ES) cells.
This method makes it possible to identify factors that function in nucleosome assembly of parental histone (H3-
H4)2. Moreover, we discovered that cells defective in parental histone transfer compromise the repression of
endogenous retrovirus (ERVs), repetitive DNA elements that are normally silenced via a heterochromatin-based
mechanism. Others show that ERV reactivation in cancer cells leads to increased response to immunotherapy.
In this proposal, we will elucidate the molecular mechanisms whereby parental (H3-H4)2 are reassembled into
nucleosomes following DNA replication in yeast and mouse ES cells and determine how deficiencies in this
process impact ERV silencing. Together, these studies will address fundamental questions regarding chromatin
replication and epigenetic inheritance, while also providing novel insights into a major epigenetic mechanism
that boosts the response of cancer cells to immunotherapy.

## Key facts

- **NIH application ID:** 10086641
- **Project number:** 2R35GM118015-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Zhiguo Zhang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $846,662
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086641

## Citation

> US National Institutes of Health, RePORTER application 10086641, Mechanism of Epigenetic Inheritance (2R35GM118015-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10086641. Licensed CC0.

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