Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis

• Published in: Nature neuroscience Vol. 20; no. 11; pp. 1520 - 1528
• Main Authors: Glasgow, Stacey M, Carlson, Jeffrey C, Zhu, Wenyi, Chaboub, Lesley S, Kang, Peng, Lee, Hyun Kyoung, Clovis, Yoanne M, Lozzi, Brittney E, McEvilly, Robert J, Rosenfeld, Michael G, Creighton, Chad J, Lee, Soo-Kyung, Mohila, Carrie A, Deneen, Benjamin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2017; Nature Publishing Group
• Subjects: 38; 38/1; 38/15; 38/77; 59; 59/5; 631/208/200; 631/378/2571/219; 631/378/2582; 631/67/70; 64/110; 64/60; 692/699/67/1922; Animal Genetics and Genomics; Animals; Base Sequence; Behavioral Sciences; Biological Techniques; Biomedicine; Brain tumors; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Care and treatment; Cell fate; Central nervous system; Chick Embryo; Chromatin; Conformation; Development and progression; Enhancers; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Genetic aspects; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Gliomas; Health aspects; In vivo methods and tests; Islet-1 protein; Male; Mice; Mice, Knockout; Mice, Transgenic; Neurobiology; Neuroglia - pathology; Neuroglia - physiology; Neuronal-glial interactions; Neurosciences; NFI Transcription Factors - biosynthesis; NFI Transcription Factors - genetics; Sox9 protein; Spinal cord; Spinal Cord - growth & development; Spinal Cord - metabolism; Spinal Cord - pathology; Transcription factors; Tumorigenesis; Tumors
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.4638

Long-range enhancer interactions regulate gene expression, yet how they influence CNS development and disease remains unclear. Glasgow et al . identified glia-specific elements and 3D chromatin architectures regulating NFIA expression during development. They also found that deletion of these enhancers suppresses NFIA expression and tumorigenesis in an in vivo glioma model. Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long-range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo . Complementary genetic studies found that Sox9–Brn2 and Isl1–Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS.