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15 páginas, 7 figuras, 3 tablas. ; Terminal differentiation programs in the nervous system are encoded by cis-regulatory elements that control the expression of terminal features of individual neuron types. We decoded the regulatory information that controls the expression of five enzymes and transporters that define the terminal identity of all eight dopaminergic neurons in the nervous system of the Caenorhabditis elegans hermaphrodite. We show that the tightly coordinated, robust expression of these dopaminergic enzymes and transporters ("dopamine pathway") is ensured through a combinatorial cis-regulatory signature that is shared by all dopamine pathway genes. This signature is composed of an Ets domain-binding site, recognized by the previously described AST-1 Ets domain factor, and two distinct types of homeodomain-binding sites that act in a partially redundant manner. Through genetic screens, we identified the sole C. elegans Distalless/Dlx ortholog, ceh-43, as a factor that acts through one of the homeodomain sites to control both induction and maintenance of terminal dopaminergic fate. The second type of homeodomain site is a Pbx-type site, which is recognized in a partially redundant and neuron subtype-specific manner by two Pbx factors, ceh-20 and ceh-40, revealing novel roles of Pbx factors in the context of terminal neuron differentiation. Taken together, we revealed a specific regulatory signature and cognate, terminal selector-type transcription factors that define the entire dopaminergic nervous system of an animal. Dopaminergic neurons in the mouse olfactory bulb express a similar combinatorial transcription factor collective of Ets/Dlx/Pbx factors, suggesting deep phylogenetic conservation of dopaminergic regulatory programs. ; This work was funded by EMBO post-doctoral fellowships and Marie Curie Funds (to M.D. and N.F.), the New York Stem Cell Foundation Fellowships and the Spanish Government (SAF2011-26273) (to N.F), the NIH (R01NS039996-05; R01NS050266-03 to O.H.; R01GM30997 to M.C.; R01GM054510 to R.S.M.; and F32GM099160 to N.A.), and the Stavanger University Hospital (to M.D.). N.F is a NARSAD Young Investigator. O.H. is an Investigator of the Howard Hughes Medical Institute. ; Peer reviewed

14 páginas, 8 figuras, 1 tabla. Material suplementario accesible online. ; Transcription factors that drive neuron type-specific terminal differentiation programs in the developing nervous system are often expressed in several distinct neuronal cell types, but to what extent they have similar or distinct activities in individual neuronal cell types is generally not well explored. We investigate this problem using, as a starting point, the C. elegans LIM homeodomain transcription factor ttx-3, which acts as a terminal selector to drive the terminal differentiation program of the cholinergic AIY interneuron class. Using a panel of different terminal differentiation markers, including neurotransmitter synthesizing enzymes, neurotransmitter receptors and neuropeptides, we show that ttx-3 also controls the terminal differentiation program of two additional, distinct neuron types, namely the cholinergic AIA interneurons and the serotonergic NSM neurons. We show that the type of differentiation program that is controlled by ttx-3 in different neuron types is specified by a distinct set of collaborating transcription factors. One of the collaborating transcription factors is the POU homeobox gene unc-86, which collaborates with ttx-3 to determine the identity of the serotonergic NSM neurons. unc-86 in turn operates independently of ttx-3 in the anterior ganglion where it collaborates with the ARID-type transcription factor cfi-1 to determine the cholinergic identity of the IL2 sensory and URA motor neurons. In conclusion, transcription factors operate as terminal selectors in distinct combinations in different neuron types, defining neuron type-specific identity features. ; This work was funded by the National Institutes of Health [R01NS039996-05 and R01NS050266-03 to O.H.; R01NS076558 to D.A.C.-R.; and R01NS070644 to R.S.M.]; a March of Dimes Foundation Grant (to D.A.C.-R.); the Spanish Government [SAF2011-26273 to N.F.]; a Marie Curie Career Integration Grant (to N.F.); a VAL i+d Fellowship from Generalitat Valenciana (to C.L.-F.); and a European Research Council Starting Grant (to N.F.). N.F. is a National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator. O.H. is an Investigator of the Howard Hughes Medical Institute. Deposited in PMC for release after 6 months. ; Peer reviewed

Platelet aggregation at the site of atherosclerotic vascular injury is the underlying pathophysiology of myocardial infarction and stroke. To build upon prior GWAS, here we report on 16 loci identified through a whole genome sequencing (WGS) approach in 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) participants deeply phenotyped for platelet aggregation. We identify the RGS18 locus, which encodes a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with expression quantitative trait loci (eQTL) signatures for RGS18 expression in platelets. Gene-based approaches implicate the SVEP1 gene, a known contributor of coronary artery disease risk. Sentinel variants at RGS18 and PEAR1 are associated with thrombosis risk and increased gastrointestinal bleeding risk, respectively. Our WGS findings add to previously identified GWAS loci, provide insights regarding the mechanism(s) by which genetics may influence cardiovascular disease risk, and underscore the importance of rare variant and regulatory approaches to identifying loci contributing to complex phenotypes. © 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. ; National Institutes of Health ; https://doi.org/10.1038/s41467-021-23470-9