Single-nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell-type-specific gene regulatory variation

Yujuan Gui, Kamil Grzyb, Mélanie H. Thomas, Jochen Ohnmacht, Pierre Garcia, Manuel Buttini, Alexander Skupin, Thomas Sauter, Lasse Sinkkonen*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Background: Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression in a cell-type-specific manner depending on the chromatin structure and accessibility. Results: We report 20,658 single-nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell-type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell-type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Conclusions: Our data set provides an extensive resource to study gene regulation in mesencephalon and provides insights into control of cell identity in the midbrain and identifies cell-type-specific regulatory variation possibly underlying phenotypic and behavioural differences between mouse strains.

Original languageEnglish
Article number43
JournalEpigenetics and Chromatin
Volume14
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

Keywords

  • Cell-type identity
  • Genetic variation
  • Midbrain
  • Mouse strains
  • Single-nuclei ATAC-seq
  • Wnt signalling

Fingerprint

Dive into the research topics of 'Single-nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell-type-specific gene regulatory variation'. Together they form a unique fingerprint.

Cite this