Functional dissection of the genomic enhancer landscapes controlling pleiotropic gene expression and mammalian heart development

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• Dr Marco Osterwalder; Department for BioMedical Research, University of Bern
• Wednesday 25 May 2022, 13:30-14:30
• Online via zoom & Kings Hedges Room .

If you have a question about this talk, please contact Bobbie Claxton.

This webinar will take place online via Zoom & Kings Hedges Room

Abstract: A significant fraction of the genetic causes underlying congenital heart disease remains poorly understood and points to defects in developmental gene regulatory networks (GRNs) that disrupt cardiac lineage decisions and morphogenesis. These GRNs are controlled by evolutionarily conserved transcription factors (TFs) which integrate cell signaling pathways and orchestrate the expression of downstream structural and functional genes. Tight spatiotemporal regulation of cardiac TFs is key in this process and is controlled by genomic cis-regulatory elements (CREs), predominantly distant-acting transcriptional enhancers. In our recent research, we have investigated the CRE architecture and chromatin topology of a gene desert flanking the SHOX2 TF associated with sino-atrial node (SAN) dysfunction and arrhythmias in humans. Using a combination of stringent epigenomic analysis, transgenic in vivo reporter assays and CRISPR -Cas9 genome editing, we defined the gene desert enhancer landscape underlying pleiotropic Shox2 expression during mouse embryogenesis. We found that the gene desert promotes craniofacial and limb development through multiple compartment-specific enhancers and is essential for embryonic survival via control of Shox2 in the sinoatrial node (SAN), which involves a cardiac CRE . In addition, while the Shox2 regulatory landscape was partitioned into largely tissue-invariant chromatin architecture, region capture Hi-C chromatin profiling uncovered an unexpected cardiac-specific contact domain within the gene desert, acting as a potential mechanism for enhancer attenuation. In summary, our results identify the Shox2 gene desert as a robust cis-regulatory hub indispensable for pleiotropic patterning and embryonic survival.

More recently, we also used multi-omics profiling at three key stages of mouse cardiac chamber development to establish the linked epigenomic and transcriptomic signatures underlying mammalian heart formation in single cells. We currently utilize the resulting gene-enhancer maps to refine the cardiac cell type-specific enhancer landscapes of the Gata4 and Hand2 TF genes, key nodes within the GRN regulating second heart field (SHF) progenitor development and essential for right ventricle and outflow tract formation. We examined the functions of multiple Gata4 and Hand2 cardiac enhancers using an enhancer loss-of-function approach and found evidence for frequent cardiac enhancer redundancy as a general mechanism providing transcriptional robustness during heart development. Our findings start to uncover the complex cis-regulatory relationships underlying cardiac TF regulation and underscore the importance of cell type-specific enhancer predictions to establish accurate mechanistic links between gene networks, heart development and clinical cardiac phenotypes in humans.

Biog: PhD in Cell Biology (2012) and Postdoctoral Researcher (2012-2014) at the Department for Biomedicine of the University of Basel, Switzerland. Postdoctoral Fellow (2014-2018) and Project Scientist (2018-2019) in the Mammalian Functional Genomics Group at Lawrence Berkeley National Laboratory (LBNL), Berkeley, California, USA . Awarded with the SNSF Eccellenza Professorial Fellowship in 2019. Since May 2020, Group Leader and Assistant Professor at the Department for BioMedical Research (DBMR) at the University of Bern, Switzerland.

The research in my group at the DBMR centers on understanding the cardiac gene regulatory mechanisms and chromatin architecture to advance our knowledge of mammalian heart development and to define new disease-relevant non-coding mutations. In particular, we are using a combination of genome engineering in mice and ES cells, single-cell applications, and functional genomics to define the cis-regulatory genomic architecture controlling expression of key cardiac transcription factors. We are also exploring strategies to study the epigenomic mechanisms promoting in-situ cardiomyocyte reprogramming for heart repair.

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This talk is part of the Babraham Seminar series.

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