transcriptional network

Causal mechanisms driving germline predisposition to myeloproliferative disorders

SUMMARY/ABSTRACT Although human genetic studies have indicated a significant hereditary predisposition to myeloproliferative neoplasms (MPNs) the underlying mechanisms driving the genetic risk remains unknown. Our large genome wide association study (GWAS) on MPNs identified several non-coding genetic risk loci associated with disease and implicated modulation of hematopoietic stem cell (HSC) self-renewal by the genetic variants. The long-term goal is to utilize our GWAS results to better understand MPN disease initiation and progression and draw out key unknown MPN predisposition genes. The overall objectives in this application are to elucidate the mechanisms by which MPN risk variants promote disease initiation and progression. The central hypothesis is that common genetic variants increase MPN risk by affecting regulatory elements that influence clonal expansion of HSCs carrying MPN driver mutations. The rationale for this project is that the HSC clones with most prevalent driver mutation found in MPN, JAK2V617F show individual specific growth rates and can develop into MPN or remain as clonal hematopoiesis without any consequences indicating that germline genetic factors influence this process. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the mechanisms by which genetic variation at the GFI1B locus influences MPN predisposition in vivo. 2) To define upstream transcriptional mechanisms disrupted by common genetic variants that predispose to MPN. Under the first aim, a newly generated mouse model will be used to evaluate clonal expansion of JAK2V617F HSCs in the context of a germline Gfi1b enhancer deletion by in vivo competitive transplantation assays. The murine studies will be complemented by an assessment of Gfi1b allele specific clonal expansion in primary human hematopoietic stem and progenitor cells (HSPCs) engineered to carry JAK2V617F mutation. Mechanistically activated mitochondrial respiration will be examined in germline enhancer inactivated JAK2V617F HSPCs in murine models and human patient samples. For the second aim, perturbation of RUNX1 bound cis-regulatory elements by MPN risk variants will be evaluated as a mechanism of clonal expansion in MPN by using lentiviral reporter assays and endogenous CRISPR/Cas9 editing approaches in primary human HSPCs and degron tagged RUNX1 cell lines. A Runx1 haploinsufficiency mouse model will be used to assess global influences of RUNX1 transcriptional network on MPN initiation. Collectively, our proposed studies aim to bridge the gap between inherited genetic variations and the clonal expansion dynamics of MPN stem cells, shedding light on crucial factors influencing disease development. The mouse models proposed in this study provide the in vivo physiological context and functional readouts required to investigate HSC clonal expansion and MPN pathogenesis.

Untitled Seminar

Laura Fenlon (Australia): Time shapes all brains: timing of a conserved transcriptional network underlies divergent cortical connectivity routes in mammalian brain development and evolution; Laurent Nguyen (Belgium): Regulation of cerebral cortex morphogenesis by migrating cells; Carol Ann Mason (USA): Wiring the eye to brain for binocular vision: lessons from the albino visual system. Thomas Perlmann (Sweden): Interrogating dopamine neuron development at the single cell level

Cell-type specific transcriptional networks related to autism

Epigenetic Reprogramming of Taste by Diet

Diets rich in sugar, salt, and fat alter taste perception and food intake, leading to obesity and metabolic disorders, but the molecular mechanisms through which this occurs are unknown. Here we show that in response to a high sugar diet, the epigenetic regulator Polycomb Repressive Complex 2.1 (PRC2.1) persistently reprograms the sensory neurons of D. melanogaster flies to reduce sweet sensation and promote obesity. In animals fed high sugar, the binding of PRC2.1 to the chromatin of the sweet gustatory neurons is redistributed to repress a developmental transcriptional network that modulates the responsiveness of these cells to sweet stimuli, reducing sweet sensation. Importantly, half of these transcriptional changes persist despite returning the animals to a control diet, causing a permanent decrease in sweet taste. Our results uncover a new epigenetic mechanism that, in response to the dietary environment, regulates neural plasticity and feeding behavior to promote obesity.

Fear circuit-based neurobehavioral signatures and transcriptional networks promoting resilience to chronic social stress