Genetic and epigenetic variation in the lineage specification of regulatory T cells.
Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease.
Immunology Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
Aaron
A
Arvey
Immunology Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
Joris
J
van der Veeken
Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, United States.|Breast Service, Memorial Sloan Kettering Cancer Center, New York, United States.
George
G
Plitas
Center for Public Health Genomics, Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, United States.
Stephen S
SS
Rich
Genetics Institute, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Florida, United States.
Patrick
P
Concannon
Immunology Program, Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, United States.|Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, United States.
Alexander Y
AY
Rudensky
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D050436:Regulatory Elements, Transcriptional; D017422:Sequence Analysis, DNA; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014158:Transcription, Genetic
epigenome; evolutionary biology; genomics; human; immune regulation; immunogenetics; immunology; mouse; regulatory T cells