A combinatorial transcription factor signature defines the HSN serotonergic neuron regulatory landscape

  1. Carla Lloret-Fernández
  2. Miren Maicas
  3. Carlos Mora-Martínez
  4. Alejandro Artacho
  5. Angela Jimeno-Martín
  6. Laura Chirivella
  7. Peter Weinberg
  8. Nuria Flames  Is a corresponding author
  1. Instituto de Biomedicina de Valencia, Spain
  2. Centro Superior de Investigación en Salud Pública, FISABIO, Spain
  3. Howard Hughes Medical Institute, Columbia University, United States

Abstract

Cell differentiation is controlled by individual transcription factors (TFs) that together activate a selection of enhancers in specific cell types. How these combinations of TFs identify and activate their target sequences remains poorly understood. Here, we identify the cis-regulatory transcriptional code that controls the differentiation of serotonergic HSN neurons in C. elegans. Activation of the HSN transcriptome is directly orchestrated by a collective of six TFs. Binding site clusters for this TF collective form a regulatory signature that is sufficient for de novo identification of HSN neuron functional enhancers. Among C. elegans neurons, the HSN transcriptome most closely resembles that of mouse serotonergic neurons. Mouse orthologs of the HSN TF collective also regulate serotonergic differentiation and can functionally substitute for their worm counterparts which suggests deep homology. Our results identify rules governing the regulatory landscape of a critically important neuronal type in two species separated by over 700 million years.

Article and author information

Author details

  1. Carla Lloret-Fernández

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Miren Maicas

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Carlos Mora-Martínez

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Alejandro Artacho

    Departamento de Genómica y Salud, Centro Superior de Investigación en Salud Pública, FISABIO, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Angela Jimeno-Martín

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Laura Chirivella

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Peter Weinberg

    Department of Biological Sciences, Howard Hughes Medical Institute, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Nuria Flames

    Developmental Neurobiology Unit, Instituto de Biomedicina de Valencia, Valencia, Spain
    For correspondence
    nflamesb@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0961-0609

Funding

Ministerio de Economía y Competitividad (SAF2014-56877-R)

  • Carla Lloret-Fernández
  • Miren Maicas
  • Carlos Mora-Martínez
  • Angela Jimeno-Martín
  • Laura Chirivella
  • Nuria Flames

European Research Council (ERC Stg 2011-281920)

  • Carla Lloret-Fernández
  • Miren Maicas
  • Carlos Mora-Martínez
  • Angela Jimeno-Martín
  • Laura Chirivella
  • Nuria Flames

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were performed according to the animal care guidelines of the European Community Council (86 ⁄ 609 ⁄ EEC) and to Spanish regulations (RD1201 ⁄ 2005), following protocols approved by the ethics committees of the Consejo Superior Investigaciones Científicas (CSIC).

Reviewing Editor

  1. Piali Sengupta, Brandeis University, United States

Publication history

  1. Received: October 20, 2017
  2. Accepted: March 16, 2018
  3. Accepted Manuscript published: March 19, 2018 (version 1)
  4. Accepted Manuscript updated: March 22, 2018 (version 2)
  5. Version of Record published: April 25, 2018 (version 3)

Copyright

© 2018, Lloret-Fernández et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Carla Lloret-Fernández
  2. Miren Maicas
  3. Carlos Mora-Martínez
  4. Alejandro Artacho
  5. Angela Jimeno-Martín
  6. Laura Chirivella
  7. Peter Weinberg
  8. Nuria Flames
(2018)
A combinatorial transcription factor signature defines the HSN serotonergic neuron regulatory landscape
eLife 7:e32785.
https://doi.org/10.7554/eLife.32785
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