Lymphocyte Identity and Genomic Switches

Naive CD4+ helper T lymphocytes can adapt to many fates upon encountering environmental stimuli and differentiate into a spectrum of effector or regulatory lineages. In the early days, immunologists defined their functionality by expression of a small handful of signature genes. With the present extraordinary capabilities to gain genome-wide information on gene transcription, chromatin state, and transcription factor recruitment, we now come to appreciate the importance of a vast majority of genomic region outside of annotated genes. This is where many regulatory elements including enhancers exist, serving as a platform for transcription factors and operating as switches for genes in proximity and at a distance. Regions of strong and extensive deposition of enhancer marks represent super-enhancers (SEs). Distinctive super-enhancer structure associates with key genes that define cell phenotype as well as highly sensitive drug targets. Accumulating evidence on chromatin state indicates that cell identity is established by converging sequential actions of pioneer transcription factors, signal-dependent transcription factors, and lineage-defining master transcription factors. Chromatin state integrates past and current action of transcription factors and presents it as epigenetic fingerprints. Deciphering fine genomic fingerprints and identifying genomic switches will pave the way for deeper understanding of identity, plasticity, and functionality of cell lineages.