Maf and Mafb control mouse pallial interneuron fate and maturation through neuropsychiatric disease gene regulation

Pai, Emily Ling-Lin; Chen, Jin; Darbandi, Siavash Fazel; Cho, Frances S.; Chen, Jiapei; Lindtner, Susan; Chu, Julia; Paz, Jeanne T.; Vogt, Daniel; Paredes, Mercedes F.; Rubenstein, John L.R.

doi:10.7554/elife.54903

Cited by 31 publications

(35 citation statements)

References 68 publications

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“…Furthermore, RFX7 directly regulates multiple transcription factors, including JUNB, KLF9, MAF, MXD4, RFX5, SOX4, SOX12, and TSC22D1, as well as chromatin modifiers, which may affect many RFX7-regulated genes that are not bound by RFX7 itself (Figure 4D , Supplementary Figure S2 ). At the same time, SOX4 and SOX12 are members of the SoxC transcription factor family with important roles in neurodevelopment ( 95 ) and, similarly, MAF (also known as c-Maf) has been shown to play a role in neuron differentiation ( 96 ). Thus, MAF, SOX4, and SOX12 may represent particularly promising links between RFX7 and its potential role in neuronal development and diseases ( 17–19 ) (Figure 6C ).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Coronel

Riege

Schwab

et al. 2021

Nucleic Acids Research

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Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.

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Section: Discussionmentioning

confidence: 99%

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Coronel

Riege

Schwab

et al. 2021

Nucleic Acids Research

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“…Sirt2 is an established transcriptional repressor (Erburu et al, 2017) that may regulate the repression of several target genes in an MGE-specific manner. Elmo1 has been previously characterized during the activity-dependent migration of CGE subtypes (De Marco García et al, 2011), and more recently predicted to be a candidate marker of immature Pvalb + interneurons in the hippocampus (Ling-Lin Pai et al, 2020). Finally, a recent study has predicted that the expression of Zcchc12 correlates with slower intrinsic firing among hippocampal CA1 interneurons (Harris et al, 2018).…”

Section: Transcription Factor Expression Is a Key Component Of Nmdar-mediated Regulation Of Mge-derived Interneuronsmentioning

confidence: 99%

NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain

Mahadevan

Mitra

Zhang

et al. 2021

Front. Mol. Neurosci.

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Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

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“…The models learned sequence patterns that matched known transcription factor binding motifs (Gupta et al, 2007). These included critical developmental transcription factors (TFs) that promote PV interneuron lineage specification Lhx6, Maf, and Mef2c (Liodis et al, 2007;Pai et al, 2020;Vogt et al, 2014) (Fig. 1g).…”

Section: Models Learn Biological Signatures Relevant For Aav Probe Designmentioning

confidence: 99%

Machine learning sequence prioritization for cell type-specific enhancer design

Lawler

Ramamurthy

Brown

et al. 2021

Preprint

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Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations, enabling characterization of their roles in behavior and in disease states. Available approaches for engineering targeted technologies for new neuron subtypes are low-yield, involving intensive transgenic strain or virus screening. Here, we introduce SNAIL (Specific Nuclear-Anchored Independent Labeling), a new virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and using them to make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV) neurons. Furthermore, we show that nuclear isolation using SNAIL in wild type mice is sufficient to capture characteristic open chromatin features of PV neurons in the cortex, striatum, and external globus pallidus. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.

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Maf and Mafb control mouse pallial interneuron fate and maturation through neuropsychiatric disease gene regulation

Cited by 31 publications

References 68 publications

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain

Machine learning sequence prioritization for cell type-specific enhancer design

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