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.

Reviewing Editor

  1. Piali Sengupta, Brandeis University, United States

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).

Version 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.

Metrics

  • 3,411
    views
  • 478
    downloads
  • 43
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.32785

Further reading

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    F Javier DeHaro-Arbona, Charalambos Roussos ... Sarah Bray
    Research Article

    Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.

    1. Developmental Biology
    Rieko Asai, Vivek N Prakash ... Takashi Mikawa
    Research Article

    Large-scale cell flow characterizes gastrulation in animal development. In amniote gastrulation, particularly in avian gastrula, a bilateral vortex-like counter-rotating cell flow, called ‘polonaise movements’, appears along the midline. Here, through experimental manipulations, we addressed relationships between the polonaise movements and morphogenesis of the primitive streak, the earliest midline structure in amniotes. Suppression of the Wnt/planar cell polarity (PCP) signaling pathway maintains the polonaise movements along a deformed primitive streak. Mitotic arrest leads to diminished extension and development of the primitive streak and maintains the early phase of the polonaise movements. Ectopically induced Vg1, an axis-inducing morphogen, generates the polonaise movements, aligned to the induced midline, but disturbs the stereotypical cell flow pattern at the authentic midline. Despite the altered cell flow, induction and extension of the primitive streak are preserved along both authentic and induced midlines. Finally, we show that ectopic axis-inducing morphogen, Vg1, is capable of initiating the polonaise movements without concomitant PS extension under mitotic arrest conditions. These results are consistent with a model wherein primitive streak morphogenesis is required for the maintenance of the polonaise movements, but the polonaise movements are not necessarily responsible for primitive streak morphogenesis. Our data describe a previously undefined relationship between the large-scale cell flow and midline morphogenesis in gastrulation.