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SUMMARY:Functional dissection of the genomic enhancer landscapes controlli
 ng pleiotropic gene expression and mammalian heart development - Dr Marco 
 Osterwalder\; Department for BioMedical Research\, University of Bern
DTSTART:20220525T123000Z
DTEND:20220525T133000Z
UID:TALK170765@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Abstract:\nA significant fraction of the genetic causes underl
 ying congenital heart disease remains poorly understood and points to defe
 cts in developmental gene regulatory networks (GRNs) that disrupt cardiac 
 lineage decisions and morphogenesis. These GRNs are controlled by evolutio
 narily conserved transcription factors (TFs) which integrate cell signalin
 g pathways and orchestrate the expression of downstream structural and fun
 ctional genes. Tight spatiotemporal regulation of cardiac TFs is key in th
 is process and is controlled by genomic cis-regulatory elements (CREs)\, p
 redominantly distant-acting transcriptional enhancers.\nIn our recent rese
 arch\, 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 g
 enome editing\, we defined the gene desert enhancer landscape underlying p
 leiotropic Shox2 expression during mouse embryogenesis. We found that the 
 gene desert promotes craniofacial and limb development through multiple co
 mpartment-specific enhancers and is essential for embryonic survival via c
 ontrol of Shox2 in the sinoatrial node (SAN)\, which involves a cardiac CR
 E. In addition\, while the Shox2 regulatory landscape was partitioned into
  largely tissue-invariant chromatin architecture\, region capture Hi-C chr
 omatin profiling uncovered an unexpected cardiac-specific contact domain w
 ithin the gene desert\, acting as a potential mechanism for enhancer atten
 uation. In summary\, our results identify the Shox2 gene desert as a robus
 t cis-regulatory hub indispensable for pleiotropic patterning and embryoni
 c survival.\n\nMore recently\, we also used multi-omics profiling at three
  key stages of mouse cardiac chamber development to establish the linked e
 pigenomic and transcriptomic signatures underlying mammalian heart formati
 on 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 fiel
 d (SHF) progenitor development and essential for right ventricle and outfl
 ow tract formation. We examined the functions of multiple Gata4 and Hand2 
 cardiac enhancers using an enhancer loss-of-function approach and found ev
 idence for frequent cardiac enhancer redundancy as a general mechanism pro
 viding transcriptional robustness during heart development. Our findings s
 tart to uncover the complex cis-regulatory relationships underlying cardia
 c TF regulation and underscore the importance of cell type-specific enhanc
 er predictions to establish accurate mechanistic links between gene networ
 ks\, heart development and clinical cardiac phenotypes in humans.\n\nBiog:
 \nPhD in Cell Biology (2012) and Postdoctoral Researcher (2012-2014) at th
 e Department for Biomedicine of the University of Basel\, Switzerland. Pos
 tdoctoral Fellow (2014-2018) and Project Scientist (2018-2019) in the Mamm
 alian Functional Genomics Group at Lawrence Berkeley National Laboratory (
 LBNL)\, Berkeley\, California\, USA. Awarded with the SNSF Eccellenza Prof
 essorial Fellowship in 2019. Since May 2020\, Group Leader and Assistant P
 rofessor at the Department for BioMedical Research (DBMR) at the Universit
 y of Bern\, Switzerland.\n\nThe research in my group at the DBMR centers o
 n understanding the cardiac gene regulatory mechanisms and chromatin archi
 tecture to advance our knowledge of mammalian heart development and to def
 ine new disease-relevant non-coding mutations. In particular\, we are usin
 g a combination of genome engineering in mice and ES cells\, single-cell a
 pplications\, 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 promo
 ting in-situ cardiomyocyte reprogramming for heart repair.\n\nClick here t
 o join live - https://us06web.zoom.us/j/88416525613  
LOCATION:Online via zoom & Kings Hedges Room 
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