Biology subjects

Sobreira, D. R.

Publications and source records attributed to Sobreira, D. R..

5 recordsLinked to original sources

bioRxiv2026

A pleiotropic EPAS1 enhancer mediating Tibetan adaptation to hypoxia is active in adipocytes

In response to hypoxic stress at high altitudes, variation at the EPAS1 locus has experienced strong selection in Tibetans. Functional dissection of the selection signals at this locus identified ENH5, an enhancer within the adaptive haplotype that has a blunted response to hypoxic stress in Tibetans. ENH5 was shown to be pleiotropic in several tissues related to hypoxia response, suggesting that a possible mechanism behind the strong selection signatures could be adaptive pleiotropy. Tibetans not only experience hypoxic conditions, but also cold temperatures due to the altitude and climate of the Tibetan Plateau. However, it is unclear whether cold temperatures affect ENH5 activity possibly contributing to the selective pressure at this locus. Here, we further characterized the role of ENH5 in subcutaneous white adipose tissue, an important tissue type that regulates body temperature in response to cold temperatures by releasing stored fat as heat through a process called thermogenesis. In this work, we investigated the role of ENH5 in adipocytes using ENH5 knockout mice (ENH5 KO), which phenocopy the reduced activity of the Tibetan allele. We show that ENH5 KO mice at normoxia and room temperature do not have significant differences in organismal phenotypes related to adiposity and metabolism compared to WT mice on a high fat diet. However, we detected effects of ENH5 conditional on thermogenic stimulation and hypoxia exposure, independently, in adipocytes cultured in vitro. Under either of these conditions, ENH5 KO has stronger differential expression of key genes involved in thermogenesis activity and adipocyte differentiation compared to WT. This differential response to thermogenic stimulation expands on the pleiotropic effects of the Tibetan ENH5 allele(s), in addition to those previously shown in well-established hypoxia-responsive tissues. Our results raise the possibility that pleiotropic effects of ENH5 may implicate unforeseen mechanisms, such as cellular energetics and thermogenesis, possibly contributing to the phenotypic adaptation to high altitude in Tibetans.

genetics↗

bioRxiv2026

Dynamic reorganization of Developmental to Adult Genome Topology Controls the Initiation and Stabilization of the Human Muscle Stem Cell State

Developmental gene expression is under tight temporal and spatial control. This regulation is imparted by tissue specific enhancers that integrate developmental signals into transcriptional responses to allow for developmental progression. Often species specific, the enhancers that regulate human muscle progenitor and stem cell gene expression are currently unknown. Here, we define the 3D chromatin organization of human muscle development and reveal key changes across the human genome that are associated with multiple layers of 3D genome reorganization during the transition from a more progenitor-like to muscle stem cell state, including a reduction of TAD numbers and an increase in CTCF binding at TAD boundaries and chromatin loops throughout developmental progression. Specifically, we found that increased CTCF occupancy at human enhancers of PAX7 in stem cells holds enhancer-promoter (e-p) loops for timely activation of PAX7 enhancers during early human development. These findings demonstrate that stem cell state acquisition is stabilized earlier than previously known and provide unprecedented insights into the initiation and control of the muscle stem cell state in humans.

developmental biology↗

bioRxiv2020

Asthma-associated variants induce IL33 differential expression through a novel regulatory region

Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as a strong regulatory element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. Supporting this notion, we show that genotype at an asthma-associated SNP, rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a novel mechanism through which a regulatory SNP contributes to genetic risk of asthma.

genomics↗

bioRxiv2020

Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

genomics↗

bioRxiv2018

A promoter interaction map for cardiovascular disease genetics

Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), however most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1,999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.

genetics↗