title: Distinct modes of SMAD2 chromatin binding and remodeling shape the transcriptional response to NODAL/Activin signaling.
abstract: NODAL/Activin signaling orchestrates key processes during embryonic development via SMAD2. How SMAD2 activates programs of gene expression that are modulated over time however, is not known. Here we delineate the sequence of events that occur from SMAD2 binding to transcriptional activation, and the mechanisms underlying them. NODAL/Activin signaling induces dramatic chromatin landscape changes, and a dynamic transcriptional network regulated by SMAD2, acting via multiple mechanisms. Crucially we have discovered two modes of SMAD2 binding. SMAD2 can bind pre-acetylated nucleosome-depleted sites. However, it also binds to unacetylated, closed chromatin, independently of pioneer factors, where it induces nucleosome displacement and histone acetylation. For a subset of genes, this requires SMARCA4. We find that long term modulation of the transcriptional responses requires continued NODAL/Activin signaling. Thus SMAD2 binding does not linearly equate with transcriptional kinetics, and our data suggest that SMAD2 recruits multiple co-factors during sustained signaling to shape the downstream transcriptional program.
authors.affiliation: Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Davide M
authors.initials: DM
authors.lastname: Coda
authors.affiliation: Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Tessa
authors.initials: T
authors.lastname: Gaarenstroom
authors.affiliation: Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.affiliation: Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom.
authors.forename: Harshil
authors.initials: H
authors.lastname: Patel
authors.affiliation: Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Daniel S J
authors.initials: DS
authors.lastname: Miller
authors.affiliation: Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Lobley
authors.affiliation: Advanced Sequencing, The Francis Crick Institute, London, United Kingdom.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom.
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Caroline S
authors.identifier: 0000-0002-8632-0480
authors.initials: CS
authors.lastname: Hill
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D055457:Nodal Protein / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D028341:Activins
keywords: NODAL/Activin; SMAD2; chromatin remodeling; chromosomes; genes; mouse; signaling dynamics; transcription