Identification of STAT5A and STAT5B target genes in human T cells.
Signal transducer and activator of transcription (STAT) comprises a family of universal transcription factors that help cells sense and respond to environmental signals. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function: their complete deficiency is lethal in mice; in humans, STAT5B deficiency alone leads to endocrine and immunological problems, while STAT5A deficiency has not been reported. STAT5A and STAT5B show peptide sequence similarities greater than 90%, but subtle structural differences suggest possible non-redundant roles in gene regulation. However, these roles remain unclear in humans. We applied chromatin immunoprecipitation followed by DNA sequencing using human CD4(+) T cells to detect candidate genes regulated by STAT5A and/or STAT5B, and quantitative-PCR in STAT5A or STAT5B knock-down (KD) human CD4(+) T cells to validate the findings. Our data show STAT5A and STAT5B play redundant roles in cell proliferation and apoptosis via SGK1 interaction. Interestingly, we found a novel, unique role for STAT5A in binding to genes involved in neural development and function (NDRG1, DNAJC6, and SSH2), while STAT5B appears to play a distinct role in T cell development and function via DOCK8, SNX9, FOXP3 and IL2RA binding. Our results also suggest that one or more co-activators for STAT5A and/or STAT5B may play important roles in establishing different binding abilities and gene regulation behaviors. The new identification of these genes regulated by STAT5A and/or STAT5B has major implications for understanding the pathophysiology of cancer progression, neural disorders, and immune abnormalities.
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America.
Takahiro
T
Kanai
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America.
Scott
S
Seki
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America.
Jennifer A
JA
Jenks
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America.
Arunima
A
Kohli
Department of Genetics, School of Medicine, Stanford University, Stanford, California, United States of America.
Trupti
T
Kawli
Department of Genetics, School of Medicine, Stanford University, Stanford, California, United States of America.
Dorrelyn Patacsil
DP
Martin
Department of Genetics, School of Medicine, Stanford University, Stanford, California, United States of America.
Michael
M
Snyder
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America ; San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
Rosa
R
Bacchetta
Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America.
Kari C
KC
Nadeau
D021581:Active Transport, Cell Nucleus; D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D016384:Consensus Sequence; D006801:Humans; D055503:Protein Multimerization; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015533:Transcriptional Activation; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins