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SUMMARY:Modelling the pathological long-range regulatory effects of struct
 ural variation with patient-specific hiPSC  - Dr. Alvaro Rada-Iglesias\; P
 rincipal Investigator – Group Leader\, Developmental Genomics Laboratory
 \, CECAD Research Centre\, University of Cologne\, Germany 
DTSTART:20181127T120000Z
DTEND:20181127T130000Z
UID:TALK108703@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Structural variants can cause congenital abnormalities by disr
 upting the 3D organization of gene regulatory landscapes. However\, elucid
 ating the pathomechanism oh human structural variation in vivo is complica
 ted by the limited access to appropriate patient material and/or the diffe
 rences in gene dosage sensitivity between mice and humans. These limitatio
 ns are well illustrated by Branchio-Oculo-Facial Syndrome (BOFS)\, a rare 
 congenital disorder caused by heterozygous mutations within TFAP2A\, a neu
 ral crest (NC) master regulator for which humans\, but not mice\, are hapl
 oinsufficient. Here we describe a unique BOFS patient carrying a de novo h
 eterozygous inversion in which one of the breakpoints is located downstrea
 m of TFAP2A\, within a large Topologically Associating Domain (TAD) which 
 we show contains distal enhancers essential for the expression of this gen
 e in human NC cells (hNCC).  Importantly\, using patient-specific hiPSC an
 d various genomic approaches\, we systematically evaluate the molecular co
 nsequences of the inversion.  \nAlthough the inversion shuffles the TFAP2A
  hNCC enhancers with potentially novel gene targets within the same TAD\, 
 this leads to neither productive enhancer-gene interactions (i.e. enhancer
  adoption) nor ectopic gains in gene expression\, illustrating how placing
  enhancers and genes within the same TAD might not be always sufficient to
  drive gene expression.  In contrast\, we conclusively demonstrate that th
 e inversion disconnects one of the TFAP2A alleles from its cognate enhance
 rs\, leading to TFAP2A monoallelic expression in hNCC.  \nIn turn\, this r
 esults in TFAP2A haploinsufficiency due to reduced TFAP2A binding to enhan
 cers controlling the expression of genes involved in craniofacial morphoge
 nesis and NCC migration. Overall\, our work illustrates the power of combi
 ning patient-specific hiPSC differentiation with different genomic and gen
 etic engineering tools to unveil the long-range pathological consequences 
 of human structural variation.
LOCATION:Babraham - The Cambridge Building\; Kings Hedges Room
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