# The impact of changes in chromatin architecture on cancer phenotypes and tumor progression

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $2,030,950

## Abstract

SUMMARY - OVERALL
Emerging data indicate that sets of genes are organized into boundary delimited territories and sub-territories,
within which there is a high level of coordination of epigenetic marks and transcriptional states. The larger
domains have been defined as compartments A and B that are respectively comprised of active and inactive
chromatin. These can be broken down into conserved TADs (topologically associated domains). The latter are
composed of highly self-interacting regions, segregated by insulated boundaries. At an even higher resolution
level, gene expression is conferred through looping of cell context specific gene enhancers to promoters within,
and less frequently beyond TAD boundaries. The most conserved TAD structural contacts are mediated and
regulated at least in part through the action of CTCF, a DNA binding TF and boundary factor, along with the
cohesin complex, while cell-type specific enhancer-promoter interactions are facilitated by cohesin, the
mediator complex and cell transcription factors. Notably, CTCF and the cohesin complex are often mutated in
cancer and play critical roles in normal development and differentiation pathways. They may also directly
interact with, or indirectly control transcription factors and histone modifying complexes linked to malignant
transformation. Based on these notions, our P01 proposes the following overall hypothesis: Somatic mutations
of CTCF or cohesin regulators disrupt the architectural organization of chromatin (affecting TAD, and sub-TAD
boundaries and enhancer interactions) and through this mechanism establish oncogenic epigenetic and
transcriptional programs. Conversely, we propose that recruitment of architectural protein complexes are also
disrupted by somatic mutation or deregulation of specific transcription factors, histone modifying enzymes and
enzymes controlling DNA methylation, which place these changes upstream of alterations in chromosome
architecture as a cause of tumorigenesis. To test our model we aim to compare the impact of mutations in
CTCF, the cohesin unloading factor PDS5B, and proteins that control enhancer function (the NOTCH1
oncogenic transcription factor, histone modifying enzymes such as Polycomb and CREBBP/EP300, as well as
enzymes that alter DNA methylation status DNMT3A). Focusing on hematologic malignancies we will: (i)
determine whether and how mutations of Ctcf and the cohesin regulatory protein, Pds5b disrupt normal
development and induce malignant transformation; (ii) determine how alterations in 3D chromosomal
architecture caused by mutation of Ctcf or the cohesin regulator, Pds5b induce tumorigenic epigenetic and
transcriptional programming; (iii) Determine whether transcription factors and mutations of epigenetic modifiers
drive malignant transformation through effects on 3D chromosomal architecture; and (iv) determine whether
drugs targeting transcription factor activity and epigenetic modifiers can `correct; the deleterious effects o...

## Key facts

- **NIH application ID:** 9952326
- **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:** $2,030,950
- **Award type:** 5
- **Project period:** 2019-06-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952326

## Citation

> US National Institutes of Health, RePORTER application 9952326, The impact of changes in chromatin architecture on cancer phenotypes and tumor progression (5P01CA229086-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952326. Licensed CC0.

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