Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Regulatory genomics of human embryonic pancreatic progenitors

ABSTRACT: Active regulatory regions in the human embryonic pancreatic progenitors were profiled by integration of transcription factor and histone modification ChIP-seq datasets. These were obtained from pancreatic progenitor cells derived in vitro from human embryonic stem cells. The purpose of this work was to study the epigenomic mechanisms involved in pancreas development.

INSTRUMENT(S): Illumina HiSeq 2000

ORGANISM(S): Homo sapiens

SUBMITTER: Jorge Ferrer

PROVIDER: E-MTAB-1990 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.

Weedon Michael N MN Cebola Ines I Patch Ann-Marie AM Flanagan Sarah E SE De Franco Elisa E Caswell Richard R Rodríguez-Seguí Santiago A SA Shaw-Smith Charles C Cho Candy H-H CH Allen Hana Lango HL Houghton Jayne Al JA Roth Christian L CL Chen Rongrong R Hussain Khalid K Marsh Phil P Vallier Ludovic L Murray Anna A Ellard Sian S Ferrer Jorge J Hattersley Andrew T AT

Nature genetics 20131110 1

The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutat ...[more]

PMID: 24212882

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Project description:The prevailing model behind synapse development and specificity is that a multitude of adhesion molecules engage in transsynaptic interactions to induce pre- and post-synaptic assembly. How these extracellular interactions translate into intracellular signal transduction for synaptic assembly remains unclear. One such complex formed by immunoglobulin superfamily member 21 (IgSF21) and neurexin2α regulates GABAergic synapse development in the mouse brain, but the precise molecular mechanisms underlying this activity remain unclear. Here, we reveal that the interaction between presynaptic Nrxn2α and postsynaptic IgSF21 is a high-affinity receptor-ligand interaction and identify a binding interface in the IgSF21-Nrxn2α complex. Despite being expressed in both dendritic and somatic regions, IgSF21 preferentially regulates dendritic GABAergic presynaptic differentiation whereas another canonical Nrxn ligand, neuroligin2 (Nlgn2), regulates primarily perisomatic presynaptic differentiation. To explore mechanisms that could underly this compartment specificity, we targeted multiple signaling pathways pharmacologically while monitoring the synaptogenic activity of IgSF21 and Nlgn2. Interestingly, both IgSF21 and Nlgn2 require c-jun N-terminal kinase (JNK)-mediated signaling, whereas Nlgn2, but not IgSF21, additionally requires CaMKII and Src kinase activity. JNK inhibition diminished de novo presynaptic differentiation without affecting the maintenance of formed synapses. We further found that Nrxn2α knockout brains exhibit altered synaptic JNK activity in a sex-specific fashion, suggesting functional linkage between Nrxns and JNK in vivo. Thus, our study elucidates the structural and functional relationship of IgSF21 with Nrxn2α and distinct signaling pathways for IgSF21 and Nlgn downstream of Nrxn2α. We therefore propose a revised hypothesis that Nrxns act as molecular hubs to specify synaptic properties not only through their multiple extracellular ligands but also through distinct intracellular signaling pathways of these ligands.

Dataset Information

Regulatory genomics of human embryonic pancreatic progenitors

Publications

Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis.

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