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Cis-regulatory architecture of a brain-signaling center predates the origin of chordates

ABSTRACT: Genomic approaches have predicted hundreds of thousands of tissue specific cis-regulatory sequences, but the determinants critical to their function and evolutionary history are mostly unknown1-4. Here, we systematically decode a set of brain enhancers active in the zona limitans intrathalamica (zli), a signaling center essential for vertebrate forebrain development via the secreted morphogen, Sonic hedgehog (Shh)5,6. We apply a de novo motif analysis tool to identify six position-independent sequence motifs together with their cognate transcription factors that are essential for zli enhancer activity and Shh expression in the mouse embryo. Using knowledge of this regulatory lexicon, we discover novel Shh zli enhancers in mice, and a functionally equivalent element in hemichordates, indicating an ancient origin of the Shh zli regulatory network that predates the chordate phylum. These findings establish a paradigm for delineating functionally conserved enhancers in the absence of overt sequence homologies, and over extensive evolutionary distances.

ORGANISM(S): Mus musculus

PROVIDER: GSE78005 | GEO | 2016/03/25

SECONDARY ACCESSION(S): PRJNA312346

REPOSITORIES: GEO

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Cis-regulatory architecture of a brain-signaling center predates the origin of chordates

Project description:Genomic approaches have predicted hundreds of thousands of tissue specific cis-regulatory sequences, but the determinants critical to their function and evolutionary history are mostly unknown1-4. Here, we systematically decode a set of brain enhancers active in the zona limitans intrathalamica (zli), a signaling center essential for vertebrate forebrain development via the secreted morphogen, Sonic hedgehog (Shh)5,6. We apply a de novo motif analysis tool to identify six position-independent sequence motifs together with their cognate transcription factors that are essential for zli enhancer activity and Shh expression in the mouse embryo. Using knowledge of this regulatory lexicon, we discover novel Shh zli enhancers in mice, and a functionally equivalent element in hemichordates, indicating an ancient origin of the Shh zli regulatory network that predates the chordate phylum. These findings establish a paradigm for delineating functionally conserved enhancers in the absence of overt sequence homologies, and over extensive evolutionary distances. Gene expression profiles from the mouse zona limitans intrathalamica (ZLI) region at E10.5

2016-03-25 | E-GEOD-78005 | biostudies-arrayexpress

Conservation of mouse-human trans-regulatory circuitry despite high cis-regulatory divergence

Project description:The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ~95% similar with that derived from human TF footprints. However, only ~20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity. We performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ~8.6 million transcription factor (TF) occupancy sites at nucleotide resolution.

2014-11-19 | E-GEOD-51341 | biostudies-arrayexpress

A new model for long-range chromatin reorganization linked to enhancer activation [Agilent_RNA]

Project description:The most prominent model for long-range enhancer regulation involves direct enhancer-promoter interaction by looping out the intervening chromatin. Using a synthetic biology approach, we have determined that a chromatin unfolding bteween Shh and its enhancers is regulated specifically by the Shh-Brain-Enhancers and is mediated by the recruitment of Poly (ADP-Ribose) Polymerase 1. This ‘chromatin unfolding’ model represents a new mechanism of long-range enhancer-promoter communication in addition to the looping and tracking models. RNA-on-chip for probing nuclear RNA on the Shh regulatory region on ESCs and NPC showed no spreading of nuclear RNA in the regulatory region upon Shh activation.

2016-11-04 | GSE89515 | GEO

A new model for long-range chromatin reorganisation linked to enhancer activation [ChIP-chip]

Project description:The most prominent model for long-range enhancer regulation involves direct enhancer-promoter interaction by looping out the intervening chromatin. Using a synthetic biology approach, we have determined that a chromatin unfolding between Shh and its enhancers is regulated specifically by the Shh-Brain-Enhancers and is mediated by the recruitment of Poly (ADP-Ribose) Polymerase 1. This ‘chromatin unfolding’ model represents a new mechanism of long-range enhancer-promoter communication in addition to the looping and tracking models. ChIP-on-chip for H3K27me3 and H3K27ac on the Shh regulatory region on ESCs and transfected ESCs showed a gain of H3k27ac specifically on active enhancers and no loss of Polycomb marks upon Shh activation.

2018-12-01 | GSE115642 | GEO

Conservation of mouse-human trans-regulatory circuitry despite high cis-regulatory divergence

2014-11-19 | GSE51341 | GEO

A new model for long-range chromatin reorganization linked to enhancer activation [Agilent_ChIP]

Project description:The most prominent model for long-range enhancer regulation involves direct enhancer-promoter interaction by looping out the intervening chromatin. Using a synthetic biology approach, we have determined that a chromatin unfolding bteween Shh and its enhancers is regulated specifically by the Shh-Brain-Enhancers and is mediated by the recruitment of Poly (ADP-Ribose) Polymerase 1. This ‘chromatin unfolding’ model represents a new mechanism of long-range enhancer-promoter communication in addition to the looping and tracking models. ChIP-on-chip for H3K27me3 on the Shh regulatory region on ESCs and transfected ESCs and NPC showed no loss of Polycomb marks upon Shh activation.

2016-11-04 | GSE89550 | GEO

cis-regulatory logic of Shh expression reveals common history of unpaired and paired fins

Project description:Despite their evolutionary, developmental, and functional importance the origin of vertebrate paired appendages remains a mystery. Classical ideas center on three hypotheses: that paired fins relate to gill arches, are derived from a fin fold, or that median fins evolved first and paired fins arose by co-option of ancient genetic patterning modules. Importantly, the third hypothesis makes specific predictions about the function and phylogenetic history of cis-regulatory elements (CREs) involved in appendage patterning. Here we show that a major enhancer for Sonic hedgehog (Shh, a key diffusible morphogen essential for proper growth and patterning of limbs and paired fins) is deeply shared between paired and unpaired fins in fish and with the limbs of mice. In mice, a single CRE termed ZRS is solely responsible for coordinating Shh expression in limbs. We use transgenic assays in zebrafish and mouse to trace the functional equivalence of the ZRS across gnathostome phylogeny and its likely absence in agnathans. CRISPR/Cas9-mediated deletion of the medaka core ZRS sequence, inspection of shh epigenetic landscape and in vivo enhancer assays reveal the existence of ZRS shadow enhancers in both teleost and human genomes. Strikingly, a complete deletion of the medaka ZRS, an experiment expected to only affect the paired fins, results in an almost complete ablation of the dorsal fin. This finding indicates that a ZRS-Shh regulatory module is shared by paired and medial fins, and that paired fins likely emerged by the co‐option of developmental programs established in the median fins of early vertebrates. Later on, this critical ZRS-driven Shh function was reinforced in pectoral fin development with the recruitment of shadow enhancers, conferring additional robustness.

2017-11-23 | GSE97860 | GEO

Chromatin proteomics reveals novel combinatorial histone modification signatures that mark distinct subpopulations of macrophage enhancers

Project description:The integrated activity of cis-regulatory elements fine-tunes transcriptional programs of mammalian cells by recruiting cell type–specific as well as ubiquitous transcription factors (TFs). Despite their key role in modulating transcription, enhancers are still poorly characterized at the molecular level, and their limited DNA sequence conservation in evolution and variable distance from target genes make their unbiased identification challenging. The coexistence of high mono-methylation and low tri-methylation levels of lysine 4 of histone H3 is considered a signature of enhancers, but a comprehensive view of histone modifications associated to enhancers is still lacking. By combining chromatin immunoprecipitation (ChIP) with mass spectrometry, we investigated cis-regulatory regions in macrophages to comprehensively identify histone marks specifically associated with enhancers, and to profile their dynamics after transcriptional activation elicited by an inflammatory stimulation. The intersection of the proteomics data with ChIP-seq and RNA-seq analyses revealed the existence of novel subpopulations of enhancers, marked by specific histone modification signatures: specifically, H3K36me2/K4me1 marks transcribed enhancers, while H3K36me3/K4me1 and H3K79me2/K4me1 combinations mark distinct classes of intronic enhancers. Thus, our MS analysis of functionally distinct genomic regions revealed the combinatorial code of histone modifications, highlighting the potential of proteomics in addressing fundamental questions in epigenetics.

2017-10-09 | PXD007582 | Pride

A bacterial global regulator forms a prion

Project description:Prions are self-propagating protein aggregates that act as protein-based genetic elements in fungi. Although prevalent in eukaryotes, prions have not been identified in bacteria. Here we demonstrate that a bacterial protein, transcription terminator Rho of Clostridium botulinum (Cb-Rho), can form a prion. Specifically, we identify a candidate prion-forming domain (cPrD) in Cb-Rho and show that it confers amyloidogenicity on Cb-Rho and can functionally replace the PrD of a yeast prion-forming protein. Furthermore, we show that its cPrD enables Cb-Rho to access alternative conformations in bacteria, a soluble form that terminates transcription efficiently and an aggregated, self-propagating prion form that is functionally compromised, causing genome-wide changes in the transcriptome. Thus, Cb-Rho functions as a protein-based genetic element in bacteria, suggesting that the emergence of prions predates the evolutionary split between eukaryotes and bacteria.

2017-02-13 | GSE90485 | GEO

EVOLUTIONARY CO-OPTION OF AN ANCESTRAL CLOACAL REGULATORY LANDSCAPE WITH THE EMERGENCE OF DIGITS AND GENITALS [ATAC-seq]

Project description:The existence of homologies between fins and tetrapod limb skeletal parts as well as of the nature of those mechanisms underlying the transition of the former towards the latter, have been a rich source of discussion for more than a century. While the recent use of gene expression patterns to try and infer evolutionary scenarios has been a popular and successful approach, in particular the distribution of Hox transcript domains, it has failed to provide clearcut evidence as to whether fishes do have bony elements related by ancestry to tetrapod hands and feet. In tetrapods, posterior Hoxd genes transcription in digits is controlled by a well-characterized series of enhancers forming a large regulatory landscape, which has its syntenic counterpart in zebrafish. We show here that the deletion of the orthologous landscape in fishes does not affect the transcription of these genes in fin buds. Instead, it abrogates hoxd expression in the cloaca, an essential structure related to the mammalian uro-genital sinus. We also report that Hoxd gene function in the mammalian uro-genital sinus depends on enhancers located in the same regulatory landscape and thus conclude that an ancestral Hox ‘cloacal’ regulation was co-opted, in tetrapod, as a playground to subsequently accompany the evolution of both external genitals and digits regulatory landscapes, along with the emergence of these developmentally and phylogenetically related structures.

2024-04-17 | GSE250263 | GEO

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