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SUMMARY:Systematically Mapping the Epigenetic Context-Dependence of Transc
 ription Factor Binding
DTSTART:20181101T120000
DTEND:20181101T130000
DTSTAMP:20260407T113711Z
UID:73c32752109b098ace9e4e308c0c838a5541646a428e7c2f17cc06f7
CATEGORIES:Conferences - Seminars
DESCRIPTION:Dr. Judith Kribelbauer\; Columbia University\, New York City\,
  NY (USA)\nBIOENGINEERING SEMINAR\n\nAbstract:\nAt the core of gene regula
 tory networks are transcription factors (TFs) that recognize specific DNA 
 sequences and target distinct gene sets. In recent years\, several high-th
 roughput methods have been developed\, providing measurements of in vitro 
 TF binding specificity for a large number of TFs. Although the resulting m
 otif models are now routinely used to inform or interpret in vivo studies\
 , it still remains challenging to predict TF binding patterns genome-wide\
 , or to distinguish between gene networks controlled by paralogous TFs or 
 those within the same structural family. One\, perhaps\, evident reason fo
 r this shortcoming is that our current models do not account for epigeneti
 c modulators of TF binding that are generally present in a cellular contex
 t\, such as DNA modifications\, cooperativity between TFs\, DNA shape\, or
  motif-flanking bases that might enhance or reduce a TF’s overall bindin
 g strength.\nTo close the gap between in vitro measured enrichment and in 
 vivo detected TF occupancy\, we have developed novel experimental and comp
 utational methods that elucidate the impact of epigenetic modulators on TF
  binding. Our results provide new insights into the array of mechanisms us
 ed by TFs to recognize DNA substrates with varying affinity\, such as posi
 tion- and paralog- specific readout of DNA modifications\, or the use of d
 istinct binding modes by multi-TF complexes. Using a D. melanogaster multi
 -homeodomain Hox complex as an example\, we show that combinatorial logic 
 in terms of complex composition and configuration is readily used to modul
 ate multi-TF binding preferences.\nWe further demonstrate how the detailed
  shape of DNA aids in creating a substrate for adaptive TF binding and how
  the mechanistic insight into such shape readout can be exploited to desig
 n TFs with unique properties\, such as the ability to differentiate betwee
 n complex compositions and configurations. Reinserting such engineered pro
 teins into the fly genome and comparing genome-wide binding patterns of 
 “wild-type” and “designer” TF together with DNA sequence and bindi
 ng site accessibility scores further allows the classification of in vivo 
 bound sites in terms of complex composition.\nBy doing so\, we obtain appr
 oximate “TF-complex-to-gene-set” mappings\, which ultimately allow inf
 erence of Hox-dependent and -independent gene regulatory networks and thei
 r associated biological functions.
LOCATION:AI 1153 https://plan.epfl.ch/?room==AI%201153
STATUS:CONFIRMED
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