Project description:High tumor mutational burden (TMB) is a predictive biomarker for the responsiveness of cancer to immune checkpoint inhibitor therapy that indicates whether immune cells can sufficiently recognize cancer cells as non-self. However, about 30% of all cancers from The Cancer Genome Atlas are classified as immune-desert tumors lacking T cell infiltration despite high TMB. Since the underlying mechanism of these immune-desert tumors has yet to be unraveled, there is a pressing need to transform such immune-desert tumors into immune-inflamed tumors and thereby enhance their responsiveness to anti-PD1 therapy. Here, we present a systems framework for identifying immuno-oncotargets, based on analysis of gene regulatory networks, and validating the effect of these targets in transforming immune-desert into immune-inflamed tumors. In particular, we identify DEAD-box helicases 54 (DDX54) as a master regulator of immune escape in immune-desert lung cancer with high TMB, and show that knockdown of DDX54 can increase immune cell infiltration and lead to improved sensitivity to anti-PD1 therapy.
Project description:Gene deserts spanning more than 500kb of non-protein coding genomic sequence are considered evolutionarily ancient and stable and are enriched in the vicinity of developmental regulator genes (Ovcharenko 2005). These extensive genomic regions typically harbor numerous conserved elements with predicted gene regulatory potential pointing to critical tissue-specific functions during development. Nevertheless, the biological necessity and underlying funtional enhancer landscapes of most gene deserts near developmental transcription factors (TFs) remain unknown, and it is unclear how precise pleiotropic expression patterns emerge from gene desert sequence. Here, we investigated the cis-regulatory architecture and function of a gene desert flanking the mouse Shox2 transcriptional regulator which itself is essential for embryonic limb, craniofacial, and cardiac pacemaker development. By combining epigenomic enhancer prediction, transgenic reporter validation and region-specific chromatin capture (C-HiC), we define the embryonic in vivo enhancer landscape and chromatin topology of the Shox2 gene desert. Targeted and context-specific genomic deletions uncover the gene desert not only as a regulator of embryonic survival through enhancer-mediated control of cardiac Shox2 expression, but also link distinct subsets of tissue-specific gene desert enhancers to the regulation of craniofacial patterning and proximal limb development. Our results hence identify the Shox2 gene desert as a fundamental genomic unit indispensable for pleiotropic patterning, robust organ morphogenesis and embryonic development progression by serving as a dynamic hub for tissue-specific developmental enhancers.
Project description:Gene deserts spanning more than 500kb of non-protein coding genomic sequence are considered evolutionarily ancient and stable and are enriched in the vicinity of developmental regulator genes (Ovcharenko 2005). These extensive genomic regions typically harbor numerous conserved elements with predicted gene regulatory potential pointing to critical tissue-specific functions during development. Nevertheless, the biological necessity and underlying funtional enhancer landscapes of most gene deserts near developmental transcription factors (TFs) remain unknown, and it is unclear how precise pleiotropic expression patterns emerge from gene desert sequence. Here, we investigated the cis-regulatory architecture and function of a gene desert flanking the mouse Shox2 transcriptional regulator which itself is essential for embryonic limb, craniofacial, and cardiac pacemaker development. By combining epigenomic enhancer prediction, transgenic reporter validation and region-specific chromatin capture (C-HiC), we define the embryonic in vivo enhancer landscape and chromatin topology of the Shox2 gene desert. Targeted and context-specific genomic deletions uncover the gene desert not only as a regulator of embryonic survival through enhancer-mediated control of cardiac Shox2 expression, but also link distinct subsets of tissue-specific gene desert enhancers to the regulation of craniofacial patterning and proximal limb development. Our results hence identify the Shox2 gene desert as a fundamental genomic unit indispensable for pleiotropic patterning, robust organ morphogenesis and embryonic development progression by serving as a dynamic hub for tissue-specific developmental enhancers.
2024-06-01 | GSE232882 | GEO
Project description:Endophytic bacteria from the desert melon
| PRJNA1199998 | ENA
Project description:Diversity of Bacteria in Desert Sands
| PRJNA437249 | ENA
Project description:Valorization of bacteria from moroccan desert
| PRJNA894224 | ENA
Project description:Bacteria in desert biological soil crusts