# Project 1: The biochemical, topological and functional impact of cancer associated Ctcfmutations and their contribution to cancer

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $417,106

## Abstract

SUMMARY – PROJECT 1 (SKOK)
It is well established that changes in cellular phenotypes that occur during development are highly
dependent on the patterning and distribution of epigenetic marks in the genome. Indeed, the major
focus of mechanistic epigenetic studies has centered around the interplay between histone or DNA
modifying proteins and transcription factors. These studies have been immensely fruitful and yielded
many fundamental insights into gene regulation in health and disease. Yet the enormous length of the
genome and the requirement for large sets of genes to be regulated and transcribed in a coordinated
manner poses significant energetic and physical challenges to cells. It is thus not surprising that an
additional critical level of control of the epigenome is conferred through the three dimensional structure
of chromosomes and their organization within the nucleus.
Though it is known that 3D genome organization plays a crucial role in gene regulation and cancer,
the underlying mechanisms connecting these are poorly understood. CTCF is central to these, as it
governs genome organization and is implicated in cancer. In fact mutations in CTCF are detected in
numerous cancers, however the extent to which they perturb 3D chromosomal architecture and
contribute to the malignant phenotype is unknown. We hypothesize that each CTCF mutation will alter
cellular function in a different manner depending on whether it is associated with (i) total loss of CTCF
binding, (ii) a change in binding affinity, (iii) an alteration in binding motif preference or (iv) orientation
of binding. Furthermore, we propose that mutations, which occur frequently in cancers that have no
apparent effect on binding or binding affinity will have important functions in disrupting dimerization of
CTCF molecules or binding of important cofactors such as cohesin. To test these models we aim to
use three innovative approaches that examine the impact of mutations on (i) binding affinity and target
sequence specificity, (ii) chromosome structure and gene regulation, and (iii) in vivo phenotype and
tumor initiation/progression. We will start by characterizing the impact of cancer associated CTCF
mutations on their binding affinity and binding motif. Next we will analyze their functional effect on cell
survival, gene expression and chromosome organization. Finally, mouse models will address the key
question of whether cancer associated CTCF mutations alone can predispose to malignant
transformation or whether cooperating mutations are required. We propose that gaining a mechanistic
predictive understanding of the impact of CTCF cancer associated mutants is essential to understand
cancer genomes. This may enable a range of novel therapeutic approaches to counteract the
malignancy effects of mutant architectural proteins.
!1

## Key facts

- **NIH application ID:** 9952330
- **Project number:** 5P01CA229086-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jane Amanda Skok
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,106
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952330

## Citation

> US National Institutes of Health, RePORTER application 9952330, Project 1: The biochemical, topological and functional impact of cancer associated Ctcfmutations and their contribution to cancer (5P01CA229086-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9952330. Licensed CC0.

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