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MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts.

Cell stem cell | 2017

Directed reprogramming of human fibroblasts into fully differentiated neurons requires massive changes in epigenetic and transcriptional states. Induction of a chromatin environment permissive for acquiring neuronal subtype identity is therefore a major barrier to fate conversion. Here we show that the brain-enriched miRNAs miR-9/9∗ and miR-124 (miR-9/9∗-124) trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9∗-124-induced neurons (miNs) are functionally excitable and uncommitted toward specific subtypes but possess open chromatin at neuronal subtype-specific loci, suggesting that such identity can be imparted by additional lineage-specific transcription factors. Consistently, we show that ISL1 and LHX3 selectively drive conversion to a highly homogeneous population of human spinal cord motor neurons. This study shows that modular synergism between miRNAs and neuronal subtype-specific transcription factors can drive lineage-specific neuronal reprogramming, providing a general platform for high-efficiency generation of distinct subtypes of human neurons.

Pubmed ID: 28886366 RIS Download

Associated grants

  • Agency: NHGRI NIH HHS, United States
    Id: U01 HG009391
  • Agency: NINDS NIH HHS, United States
    Id: DP2 NS083372
  • Agency: NHGRI NIH HHS, United States
    Id: R01 HG007175
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK050306
  • Agency: NCI NIH HHS, United States
    Id: U01 CA200060
  • Agency: NIGMS NIH HHS, United States
    Id: R25 GM086262
  • Agency: NIEHS NIH HHS, United States
    Id: R01 ES024992
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM081739
  • Agency: NIDA NIH HHS, United States
    Id: R25 DA027995
  • Agency: NIEHS NIH HHS, United States
    Id: U24 ES026699
  • Agency: NHGRI NIH HHS, United States
    Id: R01 HG007354

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This is a list of tools and resources that we have found mentioned in this publication.


Trim Galore (tool)

RRID:SCR_011847

Software tool to automate quality and adapter trimming as well as quality control, with some added functionality to remove biased methylation positions for RRBS sequence files for directional, non-directional or paired-end sequencing. Wrapper around Cutadapt and FastQC to consistently apply adapter and quality trimming to FastQ files, with extra functionality for Reduced Representation Bisulfite Sequencing data.

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RRID:SCR_014402

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RRID:SCR_014583

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RRID:SCR_016368

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RRID:SCR_015899

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RRID:SCR_005476

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RRID:SCR_004463

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RRID:AB_2079751

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RRID:AB_2313556

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Dynamic Regulatory Events Miner (data processing software)

RRID:SCR_003080

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HTSeq (software resource)

RRID:SCR_005514

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RRID:SCR_006525

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RRID:SCR_012802

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GraphPad Prism (software resource)

RRID:SCR_002798

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RRID:SCR_011323

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RRID:CVCL_2A55

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GM02171 (cell line)

RRID:CVCL_1H55

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RRID:IMSR_JAX:030273

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RRID:IMSR_JAX:030250

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