Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes

Begüm Aydin, Akshay Kakumanu, Mary Rossillo, Mireia Moreno-Estellés, Görkem Garipler, Niels Ringstad, Nuria Flames, Shaun Mahony, Esteban Mazzoni

Research output: Contribution to journalArticle

Abstract

Developmental programs that generate the astonishing neuronal diversity of the nervous system are not completely understood and thus present a major challenge for clinical applications of guided cell differentiation strategies. Using direct neuronal programming of embryonic stem cells, we found that two main vertebrate proneural factors, Ascl1 and neurogenin 2 (Neurog2), induce different neuronal fates by binding to largely different sets of genomic sites. Their divergent binding patterns are not determined by the previous chromatin state, but are distinguished by enrichment of specific E-box sequences that reflect the binding preferences of the DNA-binding domains. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity profiles that differentially shape the binding of downstream transcription factors during neuronal differentiation. This study provides a mechanistic understanding of how transcription factors constrain terminal cell fates, and it delineates the importance of choosing the right proneural factor in neuronal reprogramming strategies.

Original languageEnglish (US)
JournalNature Neuroscience
DOIs
StatePublished - Jan 1 2019

Fingerprint

Chromatin
Transcription Factors
E-Box Elements
Embryonic Stem Cells
Nervous System
Vertebrates
Cell Differentiation
DNA

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes. / Aydin, Begüm; Kakumanu, Akshay; Rossillo, Mary; Moreno-Estellés, Mireia; Garipler, Görkem; Ringstad, Niels; Flames, Nuria; Mahony, Shaun; Mazzoni, Esteban.

In: Nature Neuroscience, 01.01.2019.

Research output: Contribution to journalArticle

Aydin, Begüm ; Kakumanu, Akshay ; Rossillo, Mary ; Moreno-Estellés, Mireia ; Garipler, Görkem ; Ringstad, Niels ; Flames, Nuria ; Mahony, Shaun ; Mazzoni, Esteban. / Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes. In: Nature Neuroscience. 2019.
@article{d6a9a711840947c19b35491e2be3fd76,
title = "Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes",
abstract = "Developmental programs that generate the astonishing neuronal diversity of the nervous system are not completely understood and thus present a major challenge for clinical applications of guided cell differentiation strategies. Using direct neuronal programming of embryonic stem cells, we found that two main vertebrate proneural factors, Ascl1 and neurogenin 2 (Neurog2), induce different neuronal fates by binding to largely different sets of genomic sites. Their divergent binding patterns are not determined by the previous chromatin state, but are distinguished by enrichment of specific E-box sequences that reflect the binding preferences of the DNA-binding domains. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity profiles that differentially shape the binding of downstream transcription factors during neuronal differentiation. This study provides a mechanistic understanding of how transcription factors constrain terminal cell fates, and it delineates the importance of choosing the right proneural factor in neuronal reprogramming strategies.",
author = "Beg{\"u}m Aydin and Akshay Kakumanu and Mary Rossillo and Mireia Moreno-Estell{\'e}s and G{\"o}rkem Garipler and Niels Ringstad and Nuria Flames and Shaun Mahony and Esteban Mazzoni",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41593-019-0399-y",
language = "English (US)",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes

AU - Aydin, Begüm

AU - Kakumanu, Akshay

AU - Rossillo, Mary

AU - Moreno-Estellés, Mireia

AU - Garipler, Görkem

AU - Ringstad, Niels

AU - Flames, Nuria

AU - Mahony, Shaun

AU - Mazzoni, Esteban

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Developmental programs that generate the astonishing neuronal diversity of the nervous system are not completely understood and thus present a major challenge for clinical applications of guided cell differentiation strategies. Using direct neuronal programming of embryonic stem cells, we found that two main vertebrate proneural factors, Ascl1 and neurogenin 2 (Neurog2), induce different neuronal fates by binding to largely different sets of genomic sites. Their divergent binding patterns are not determined by the previous chromatin state, but are distinguished by enrichment of specific E-box sequences that reflect the binding preferences of the DNA-binding domains. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity profiles that differentially shape the binding of downstream transcription factors during neuronal differentiation. This study provides a mechanistic understanding of how transcription factors constrain terminal cell fates, and it delineates the importance of choosing the right proneural factor in neuronal reprogramming strategies.

AB - Developmental programs that generate the astonishing neuronal diversity of the nervous system are not completely understood and thus present a major challenge for clinical applications of guided cell differentiation strategies. Using direct neuronal programming of embryonic stem cells, we found that two main vertebrate proneural factors, Ascl1 and neurogenin 2 (Neurog2), induce different neuronal fates by binding to largely different sets of genomic sites. Their divergent binding patterns are not determined by the previous chromatin state, but are distinguished by enrichment of specific E-box sequences that reflect the binding preferences of the DNA-binding domains. The divergent Ascl1 and Neurog2 binding patterns result in distinct chromatin accessibility and enhancer activity profiles that differentially shape the binding of downstream transcription factors during neuronal differentiation. This study provides a mechanistic understanding of how transcription factors constrain terminal cell fates, and it delineates the importance of choosing the right proneural factor in neuronal reprogramming strategies.

UR - http://www.scopus.com/inward/record.url?scp=85065785244&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065785244&partnerID=8YFLogxK

U2 - 10.1038/s41593-019-0399-y

DO - 10.1038/s41593-019-0399-y

M3 - Article

JO - Nature Neuroscience

JF - Nature Neuroscience

SN - 1097-6256

ER -