4.7 Article

Integrated Epigenetic Mapping of Human and Mouse Salivary Gene Regulation

Journal

JOURNAL OF DENTAL RESEARCH
Volume 98, Issue 2, Pages 209-217

Publisher

SAGE PUBLICATIONS INC
DOI: 10.1177/0022034518806518

Keywords

salivary glands; gene expression regulation; systems biology; gene regulatory networks; messenger RNA; exocrine glands

Funding

  1. Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health [JAC Z01 DE00695]
  2. NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [ZIADE000695] Funding Source: NIH RePORTER

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Significant effort has been applied to identify the genome-wide gene expression profiles associated with salivary gland development and pathophysiology. However, relatively little is known about the regulators that control salivary gland gene expression. We integrated data from DNase1 digital genomic footprinting, RNA-seq, and gene expression microarrays to comprehensively characterize the cis- and trans-regulatory components controlling gene expression of the healthy submandibular salivary gland. Analysis of 32 human tissues and 87 mouse tissues was performed to identify the highly expressed and tissue-enriched transcription factors driving salivary gland gene expression. Following RNA analysis, protein expression levels and subcellular localization of 39 salivary transcription factors were confirmed by immunohistochemistry. These expression analyses revealed that the salivary gland highly expresses transcription factors associated with endoplasmic reticulum stress, human T-cell lymphotrophic virus 1 expression, and Epstein-Barr virus reactivation. DNase1 digital genomic footprinting to a depth of 333,426,353 reads was performed and utilized to generate a salivary gland gene regulatory network describing the genome-wide chromatin accessibility and transcription factor binding of the salivary gland at a single-nucleotide resolution. Analysis of the DNase1 gene regulatory network identified dense interconnectivity among PLAG1, MYB, and 13 other transcription factors associated with balanced chromosomal translocations and salivary gland tumors. Collectively, these analyses provide a comprehensive atlas of the cis- and trans-regulators of the salivary gland and highlight known aberrantly regulated pathways of diseases affecting the salivary glands.

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