Epigenetic transcriptional control of intestinal epithelial regionality

• Applicant: Judith Kraiczy, Ph.D.
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology ; Gastroenterology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444801317

Diverse cellular identities are essential for tissue functions, but the molecular mechanisms that maintain adult cell-specific transcriptional programs are poorly understood. In the mammalian digestive tract, distinct regions of the small and large intestines remain remarkably stable, whilst aberrations in regional identity (metaplasia) are associated with disease. Here, I propose to identify epigenetic and transcriptional determinants of anterior-posterior gut epithelial regionality. I will also investigate how exactly these rules are violated in a mouse model where adult colonic epithelium abruptly acquires all properties of the small intestine. By profiling region-specific chromatin accessibility (ATAC-seq), histone modifications (ChIP-seq), and gene expression (RNA-seq), I will first delineate the enhancers and transcription factors (TFs) associated with intestinal stem cells purified from wild-type mouse small (duodenum, jejunum and ileum) and large (cecum and colon) intestines. Using intestinal stem cell-derived organoids, I will then examine the functions of candidate TFs in maintaining regionality. These studies centre on TF roles in producing and maintaining stable chromatin states. Second, the host laboratory has found that loss of a single colon-restricted TF, SATB2, causes phenotypic and transcriptional conversion of colonic into ileal epithelium. My preliminary data indicate that this transformation involves extensive rewiring of accessible chromatin. By mapping chromatin accessibility and genome-wide SATB2-binding over time, in response to acute SATB2 loss and forced expression, I will investigate the sequence of epigenetic events to explain how SATB2 drives posterior identity. These findings have implications for understanding how epigenetic mechanism maintain stable cell identities that may be perturbed in human disease.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Ramesh Shivdasani, Ph.D.