title: Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells.
abstract: Spatially distinct gene expression profiles in neural stem cells (NSCs) are a prerequisite to the formation of neuronal diversity, but how these arise from the regulatory interactions between chromatin accessibility and transcription factor activity has remained unclear. Here, we demonstrate that, despite their distinct gene expression profiles, NSCs of the mouse cortex and spinal cord share the majority of their DNase I hypersensitive sites (DHSs). Regardless of this similarity, domain-specific gene expression is highly correlated with the relative accessibility of associated DHSs, as determined by sequence read density. Notably, the binding pattern of the general NSC transcription factor SOX2 is also largely cell type specific and coincides with an enrichment of LHX2 motifs in the cortex and HOXA9 motifs in the spinal cord. Interestingly, in a zebrafish reporter gene system, these motifs were critical determinants of patterned gene expression along the rostral-caudal axis. Our findings establish a predictive model for patterned NSC gene expression, whereby domain-specific expression of LHX2 and HOX proteins act on their target motifs within commonly accessible cis-regulatory regions to specify SOX2 binding. In turn, this binding correlates strongly with these DHSs relative accessibility-a robust predictor of neighboring gene expression.
authors.affiliation: Ludwig Institute for Cancer Research, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Hagey
authors.affiliation: Ludwig Institute for Cancer Research, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Cécile
authors.initials: C
authors.lastname: Zaouter
authors.affiliation: Ludwig Institute for Cancer Research, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Combeau
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Monika Andersson
authors.initials: MA
authors.lastname: Lendahl
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Olov
authors.initials: O
authors.lastname: Andersson
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna, SE-17121, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Huss
authors.affiliation: Ludwig Institute for Cancer Research, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Jonas
authors.initials: J
authors.lastname: Muhr
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002843:Chromatin / Q000378:metabolism*; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D058953:Neural Stem Cells / Q000502:physiology*; D011485:Protein Binding; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D029961:Zebrafish Proteins; C097899:homeobox protein HOXA9