DNase i hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements

Matthew S. Wilken, Joseph A. Brzezinski, Anna La Torre Vila, Kyle Siebenthall, Robert Thurman, Peter Sabo, Richard S. Sandstrom, Jeff Vierstra, Theresa K. Canfield, R. Scott Hansen, Michael A. Bender, John Stamatoyannopoulos, Thomas A. Reh

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background: The brain, spinal cord, and neural retina comprise the central nervous system (CNS) of vertebrates. Understanding the regulatory mechanisms that underlie the enormous cell-type diversity of the CNS is a significant challenge. Whole-genome mapping of DNase I-hypersensitive sites (DHSs) has been used to identify cis-regulatory elements in many tissues. We have applied this approach to the mouse CNS, including developing and mature neural retina, whole brain, and two well-characterized brain regions, the cerebellum and the cerebral cortex. Results: For the various regions and developmental stages of the CNS that we analyzed, there were approximately the same number of DHSs; however, there were many DHSs unique to each CNS region and developmental stage. Many of the DHSs are likely to mark enhancers that are specific to the specific CNS region and developmental stage. We validated the DNase I mapping approach for identification of CNS enhancers using the existing VISTA Browser database and with in vivo and in vitro electroporation of the retina. Analysis of transcription factor consensus sites within the DHSs shows distinct region-specific profiles of transcriptional regulators particular to each region. Clustering developmentally dynamic DHSs in the retina revealed enrichment of developmental stage-specific transcriptional regulators. Additionally, we found reporter gene activity in the retina driven from several previously uncharacterized regulatory elements surrounding the neurodevelopmental gene Otx2. Identification of DHSs shared between mouse and human showed region-specific differences in the evolution of cis-regulatory elements. Conclusions: Overall, our results demonstrate the potential of genome-wide DNase I mapping to cis-regulatory questions regarding the regional diversity within the CNS. These data represent an extensive catalogue of potential cis-regulatory elements within the CNS that display region and temporal specificity, as well as a set of DHSs common to CNS tissues. Further examination of evolutionary conservation of DHSs between CNS regions and different species may reveal important cis-regulatory elements in the evolution of the mammalian CNS.

Original languageEnglish (US)
Article number8
JournalEpigenetics and Chromatin
Volume8
Issue number1
DOIs
StatePublished - Feb 28 2015
Externally publishedYes

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Deoxyribonucleases
Nucleic Acid Regulatory Sequences
Deoxyribonuclease I
Retina
Hypersensitivity
Central Nervous System
Brain
Nerve Tissue
Electroporation
Chromosome Mapping
Temporal Lobe
Reporter Genes
Cerebral Cortex
Cerebellum
Cluster Analysis
Vertebrates
Spinal Cord
Transcription Factors
Genome
Databases

Keywords

  • Central nervous system
  • Cis-regulation
  • DNase-seq
  • Retina

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology

Cite this

DNase i hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements. / Wilken, Matthew S.; Brzezinski, Joseph A.; La Torre Vila, Anna; Siebenthall, Kyle; Thurman, Robert; Sabo, Peter; Sandstrom, Richard S.; Vierstra, Jeff; Canfield, Theresa K.; Hansen, R. Scott; Bender, Michael A.; Stamatoyannopoulos, John; Reh, Thomas A.

In: Epigenetics and Chromatin, Vol. 8, No. 1, 8, 28.02.2015.

Research output: Contribution to journalArticle

Wilken, MS, Brzezinski, JA, La Torre Vila, A, Siebenthall, K, Thurman, R, Sabo, P, Sandstrom, RS, Vierstra, J, Canfield, TK, Hansen, RS, Bender, MA, Stamatoyannopoulos, J & Reh, TA 2015, 'DNase i hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements', Epigenetics and Chromatin, vol. 8, no. 1, 8. https://doi.org/10.1186/1756-8935-8-8
Wilken, Matthew S. ; Brzezinski, Joseph A. ; La Torre Vila, Anna ; Siebenthall, Kyle ; Thurman, Robert ; Sabo, Peter ; Sandstrom, Richard S. ; Vierstra, Jeff ; Canfield, Theresa K. ; Hansen, R. Scott ; Bender, Michael A. ; Stamatoyannopoulos, John ; Reh, Thomas A. / DNase i hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements. In: Epigenetics and Chromatin. 2015 ; Vol. 8, No. 1.
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AU - Thurman, Robert

AU - Sabo, Peter

AU - Sandstrom, Richard S.

AU - Vierstra, Jeff

AU - Canfield, Theresa K.

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