BMP–SATB2 Regulation of Colonic Epithelium Patterning and Development

Jorge Mùnera, Ph.D.

Research Project Leader
Department of Regenerative Medicine and Cell Biology

Overview

Dr. Munera’s research focused on defining the molecular mechanisms that establish and maintain regional identity in the developing human colon. Using human pluripotent stem cell-derived organoids, this work investigated how bone morphogenetic protein (BMP) signaling directs hindgut differentiation and induces the colon-specific transcription factor SATB2.

The central hypothesis proposed that BMP-dependent SMAD signaling activates SATB2 and related transcriptional programs, which remodel chromatin and establish a gene expression profile characteristic of colonic epithelium.

This project provided a mechanistic framework linking developmental signaling pathways to epithelial identity and disease susceptibility in ulcerative colitis and colorectal cancer.

Specific Aims

• Define how BMP–SMAD signaling regulates early transcriptional programs driving colonic specification
• Determine how SATB2 controls chromatin remodeling and gene expression required for colonic epithelial identity

Research Approach

The project leveraged human pluripotent stem cell-derived colonic organoids (HCOs) as a physiologically relevant model of human colon development. Gain- and loss-of-function approaches targeting BMP signaling and SMAD transcription factors were used to identify early patterning events during differentiation. Genome-wide analyses, including RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq), were employed to define transcriptional and epigenetic programs. Complementary experiments manipulated SATB2 expression to determine its role in chromatin organization and repression of small intestinal gene programs. These studies integrated developmental biology, stem cell modeling, and epigenetic analysis to define mechanisms of tissue specification.

Use of the Center's Core Resources

Cell Models Core

• Generation and gene editing of human pluripotent stem cells and organoids

Advanced Imaging Core

• Organoid imaging and structural analysis

Animal Models Core

• Organoid transplantation and in vivo validation

Innovation

• Introduces human colonic organoids as a model for studying early gastrointestinal development
• Identifies BMP–SMAD signaling as a key regulator of colon-specific transcriptional programs
• Defines SATB2 as a central chromatin organizer driving colonic epithelial identity

Impact and Outcomes

This project established a mechanistic link between developmental signaling pathways and adult disease susceptibility by defining how colonic identity is specified at the molecular level. The findings provided new insight into how disruptions in epithelial patterning contribute to ulcerative colitis and colorectal cancer.

By developing advanced human organoid models and integrating epigenetic analyses, this work positioned Dr. Munera as a leader in gastrointestinal developmental biology and supported the transition to an independent research program focused on colon biology and disease.