Manuel Mattheisen

Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • John F. Fullard, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Dept Psychiat
  • ,
  • Claudia Giambartolomei, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Dept Psychiat
  • ,
  • Mads E. Hauberg
  • Ke Xu, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Inst Genom & Multiscale Biol
  • ,
  • Georgios Voloudakis, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Dept Psychiat
  • ,
  • Zhiping Shao, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Ctr Mol Biol & Genet Neurodegenerat
  • ,
  • Christopher Bare, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Flow Cytometry Ctr Res Excellence
  • ,
  • Joel T. Dudley, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Inst Genom & Multiscale Biol
  • ,
  • Manuel Mattheisen
  • Nikolaos K. Robakis, Icahn Sch Med Mt Sinai, Icahn School of Medicine at Mount Sinai, Ctr Mol Biol & Genet Neurodegenerat
  • ,
  • Vahram Haroutunian, James J Peters VA Med Ctr, James J. Peters VA Medical Center, US Department of Veteran Affairs, Mental Illness Res Educ & Clin Ctr VISN South 2
  • ,
  • Panos Roussos, James J Peters VA Med Ctr, James J. Peters VA Medical Center, US Department of Veteran Affairs, Mental Illness Res Educ & Clin Ctr VISN South 2

Open chromatin provides access to DNA-binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. To better understand the role of CREs in neuropsychiatric disorders we applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to neuronal and non-neuronal nuclei isolated fromfrozen postmortem human brain by fluorescence-activated nuclear sorting (FANS). Most of the identified open chromatin regions (OCRs) are differentially accessible between neurons and non-neurons, and show enrichment with known cell typemarkers, promoters and enhancers. Relative to those of non-neurons, neuronal OCRs aremore evolutionarily conserved and are enriched in distal regulatory elements. Transcription factor (TF) footprinting analysis identifies differences in the regulome between neuronal and non-neuronal cells and ascribes putative functional roles to a number of non-coding schizophrenia (SCZ) risk variants. Among the identified variants is a Single Nucleotide Polymorphism(SNP) proximal to the gene encoding SNX19. In vitro experiments reveal that this SNP leads to an increase in transcriptional activity. As elevated expression of SNX19 has been associated with SCZ, our data provide evidence that the identified SNP contributes to disease. These results represent the first analysis of OCRs and TF-binding sites in distinct populations of postmortemhuman brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.

Original languageEnglish
JournalHuman Molecular Genetics
Volume26
Issue10
Pages (from-to)1942-1951
Number of pages10
ISSN0964-6906
DOIs
Publication statusPublished - 15 May 2017

    Research areas

  • GENOME-WIDE ASSOCIATION, ASSEMBLY PROTEIN AP180, EMBRYONIC STEM-CELLS, TRANSCRIPTION FACTOR, SUSCEPTIBILITY LOCI, ALZHEIMERS-DISEASE, NEURONAL-ACTIVITY, EXPRESSION, RISK, DIFFERENTIATION

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