Biology subjects

Pelonero, A.

Publications and source records attributed to Pelonero, A..

3 recordsLinked to original sources

bioRxiv2023

Chromatin Remodeling Drives Immune-Fibroblast Crosstalk in Heart Failure Pathogenesis

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1-positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

molecular biology↗

bioRxiv2022

Single Cell Epigenetics Reveal Cell-Cell Communication Networks in Normal and Abnormal Cardiac Morphogenesis

Communication between myriad cell types during organ formation underlies proper morphogenesis1. In cardiac development, reciprocal signaling between mesoderm progenitors and neural crest cells is essential, and its disruption leads to congenital heart malformations, the most common human birth defect. However, mechanistic interrogation of temporal gene networks and cis regulatory elements in this crosstalk is limited2,3. Here, we integrated single cell chromatin accessibility and transcriptomics to establish an unbiased and temporal epigenomic map of the embryonic mouse heart over multiple stages and developed machine learning models to predict enhancers for heart and neural crest. We leveraged these advances to determine the consequences of dysregulated signaling at single cell resolution caused by deletion of TBX1, a transcription factor that causes morphogenetic defects of the cardiac outflow tract in humans and functions non-cell autonomously in cardiac mesodermal progenitors to direct pharyngeal neural crest differentiation4-6. Loss of Tbx1 in mice led to broad closure of chromatin regions enriched in cardiac progenitor transcription factor motifs within a narrow subset of cardiac mesodermal progenitors and correlated with diminished expression of numerous members of the fibroblast growth factor, retinoic acid, Notch and Semaphorin pathways. In affected progenitors, ectopic accessibility and expression of posterior heart field factors in the anterior heart field suggested impaired axial patterning. In response, a subset of cardiac neural crest cells displayed epigenomic and transcriptional defects, indicating a failure of differentiation corresponding to dysregulation of the anterior-posterior gradient of pharyngeal Hox gene expression. This study demonstrates that single-cell genomics and machine learning can generate a mechanistic model for how disruptions in cell communication selectively affect spatiotemporally dynamic regulatory networks in cardiogenesis.

developmental biology↗

bioRxiv2022

Single Cell Multimodal Analyses Reveal Epigenomic and Transcriptomic Basis for Birth Defects in Maternal Diabetes

Birth defects occur in [~]6% of all live births and can be caused by combinations of genetic and environmental influences1. Large-scale DNA sequencing efforts are revealing genetic influences2,3, but investigations into the contributions of environmental factors have largely been limited to association studies with limited mechanistic insight. Hyperglycemia present in pre-gestational diabetic mothers is among the most frequent environmental contributor to congenital defects and results in an increased incidence of congenital heart defects and craniofacial anomalies4. However, the cell types involved and underlying mechanisms by which maternal hyperglycemia affects these regions are unknown. Here, we utilized multi-modal single cell analyses to reveal that maternal diabetes affects the epigenomic and transcriptomic state of specific subsets of cardiac and craniofacial progenitors during embryogenesis. A previously unrecognized subpopulation of anterior heart field progenitors expressing Alx3 acquired a more posterior identity in response to maternal hyperglycemia, based on gene expression and chromatin status. Similarly, a sub-population of neural crest-derived cells in the second pharyngeal arch, which contributes to craniofacial structures, also displayed abnormalities in cell specification and patterning. Analysis of differentially accessible chromatin regions demonstrated that disrupted patterning was associated with increased intrinsic retinoic acid signaling in affected cell types in response to maternal diabetes and hyperglycemia. This work demonstrates how an environmental insult can have highly selective epigenomic consequences on discrete cell types leading to developmental patterning defects.

developmental biology↗