Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming.
Pro-neural transcription factors and small molecules can induce the reprogramming of fibroblasts into functional neurons; however, the immediate-early molecular events that catalyze this conversion have not been well defined. We previously demonstrated that neurogenin 2 (NEUROG2), forskolin (F), and dorsomorphin (D) can reprogram fibroblasts into functional neurons with high efficiency. Here, we used this model to define the genetic and epigenetic events that initiate an acquisition of neuronal identity. We demonstrate that NEUROG2 is a pioneer factor, FD enhances chromatin accessibility and H3K27 acetylation, and synergistic transcription activated by these factors is essential to successful reprogramming. CREB1 promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma cell and skin fibroblast reprogramming can be improved using SOX4 or chromatin-modifying chemicals.
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Derek K
DK
Smith
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Jianjing
J
Yang
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Meng-Lu
ML
Liu
Department of Molecular Biology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA; Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA. Electronic address: chun-li.zhang@utsouthwestern.edu.
Chun-Li
CL
Zhang
D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D054338:Cell Transdifferentiation / Q000235:genetics; D065150:Cellular Reprogramming; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D016000:Cluster Analysis; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
D051792:Basic Helix-Loop-Helix Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D006657:Histones; D009419:Nerve Tissue Proteins; D055751:SOXC Transcription Factors; C115163:CREB1 protein, human; C491183:NEUROG2 protein, human; C517757:PRKACA protein, human
ATAC-seq; CREB1; ChIP-seq; NEUROG2; RNA-seq; SOX4; SWI/SNF; reprogramming; small molecules; transdifferentiation