Lineage master regulator and cancer-selective partner transcription factors rewire 3D genome topology for tumor-specific gene control

Sep 23, 2026

Lineage-determining transcription factors can establish normal tissue identity yet also drive carcinogenesis, and the epigenetic basis for this switch has been unclear. This study shows that p63 reorganizes three-dimensional chromatin topology in squamous cell carcinoma by cooperating with the tumor-selective partner FOXK1. Multi-omic profiling reveals increased enhancer connectivity to oncogene-proximal cis-regulatory elements and a secondary enhancer-looping architecture. FOXK1 loss weakens p63-dependent loops and reduces transcription of target genes. The p63–FOXK1 interaction appears in human tumors but not normal tissues.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages24

Reading Time1 h 0 min

AccessFree to download

Introduction

Lineage TF reprogramming in cancer

3D chromatin dynamics and enhancer-promoter contacts

p63 as pioneer and oncogenic TF

Context-specific partners and the need for discovery

Results (partial excerpt)

p63 cooperation with FOXK1 in SCC

Multi-omic evidence and enhancer-loop architecture

FOXK1-dependent regulation and tumor specificity

CANCER Lineage master regulator and cancer-selective partner transcription factors rewire 3D genome topology for tumor-specific gene control Namyoung Jung1*†, Vanessa Lopez-Pajares1†, Laura K.H. Donohue1,2, Margaret G. Guo1,3, Suhas Srinivasan1, Zurab Siprashvili1, Paul A. Khavari1,4,5* Lineage-determining transcription factors (TFs), such as p63 in epithelial tissues, establish normal tissue identity but can also drive carcinogenesis. The epigenetic basis for these divergent effects, however, is unclear. Here, we show that p63 reorganizes three-dimensional (3D) chromatin topology in squamous cell carcinoma (SCC) through cooperation with the tumor-selective partner TF, FOXK1. Multi-omic profiling across normal and malignant states reveals that p63 enhances connectivity between cis-regulatory elements near oncogenesand promotes a secondary enhancer looping architecture, in which p63 and FOXK1-enriched enhancers indirectly contact target promoters via FOXK1-associated intermediate anchors lacking p63 binding. FOXK1 mediates p63-dependent chromatin looping, as FOXK1 loss selectively weakens p63-dependent loops and reduces transcription of associated target genes. The p63–FOXK1 interaction is observed in human tumor samples but not in normal tissues. Together, our findings define an epigenetic mechanism by which a lineage master TF and tumor-restricted partner TF reshape 3D chromatin structure to drive oncogenic transcription, with implications for tumor cell identity and therapy. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Cancer cells frequently reprogram core transcriptional regulatory circuits established by lineage-specifying master transcription factors (TFs), repurposing them to sustain tumor growth and survival (1–3). These lineage TFs are not only essential for defining and maintaining normal tissue identity but also play central roles in establishing and reinforcing cancer cell lineage identity. In aggressive tumors, lineage identity programs become pathologically reactivated or reconfigured, enabling tumor cells to adopt distinct transcriptional states that promote malignancy and therapeutic resistance. For instance, in pancreatic ductal adenocarcinoma (PDAC), aberrant expression of the squamous lineage TF p63 drives a shift toward a basal-like identity, reshaping enhancer landscapes and conferring chemoresistance (4) . These tumor lineage identities are often maintained through context-specific cooperation between lineage TFsand chromatin interactors, which together establish tumor-specific regulatory circuits (5). Understanding how such TF–interactor partnerships rewire chromatin architecture and gene networks is a fundamental question in cancer biology, as these mechanisms not only enforce cancer-specific lineage identity but also distinguish malignant from normal cell states. Decoding these tumor-selective regulatory strategies holds direct implications for overcoming therapeutic resistance and developing precision therapies that spare normal tissue function (6) . Master lineage TFs maintain cell identity, in part, by regulating 3D chromatin dynamics, including enhancer-promoter (E-P) contacts (2, 7, 8) . Lineage TFs bind to tissue-specific cis-regulatory elements 1Program in epithelial Biology, Stanford University School of Medicine, Stanford, cA, USA. 2department of Genetics, Stanford University, Stanford, cA, USA. 3Stanford Program in Biomedical informatics, Stanford University, Stanford, cA, USA. 4Stanford Program in cancer Biology, Stanford University, Stanford, cA, USA. 5veterans Affairs Palo Alto healthcare System, Palo Alto, cA, USA. *corresponding [author. email:](author. email:) [jnamyoung@gmail.com](jnamyoung@gmail.com) (n.J.); khavari@stanford. edu (P.A. K.) †th

FAQs

What role does p63 play in normal tissue identity and cancer?

p63 is a lineage master transcription factor that establishes normal epithelial identity and differentiation. In squamous cell carcinomas, p63 can act as a master oncogenic factor promoting aggressive tumor behaviors.

How do p63 and FOXK1 cooperate to control 3D genome topology?

p63 reorganizes 3D chromatin topology in SCC through cooperation with the tumor-selective partner FOXK1. The study links this to enhanced connectivity between regulatory elements and a secondary enhancer-looping architecture involving FOXK1-associated intermediate anchors.

What happens to p63-dependent chromatin loops and target gene transcription when FOXK1 is lost?

FOXK1 loss selectively weakens p63-dependent chromatin loops and reduces transcription of associated target genes, supporting FOXK1 as a mediator of p63-dependent looping.

Sep 23, 2026

Uploaded by PakDamar76