Biology subjects

Broberg, C.

Publications and source records attributed to Broberg, C..

3 recordsLinked to original sources

bioRxiv2025

Maternal obesity programs cardiac remodeling in offspring via epigenetic, metabolic, and immune dysregulations.

Maternal obesity during pregnancy predisposes the offspring to a high risk of developing cardiovascular and metabolic diseases later in life. This study investigated cardiac perturbations caused by maternal obesity by utilizing a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic abnormalities observed in humans. Our study revealed that offspring of HFD-fed mothers (Off-HFD) exhibit a progression of obesity, dyslipidemia, and metabolic inflexibility when compared with offspring of regular diet-fed mothers (Off-RD). Deeper investigation of cardiac function revealed profound functional, metabolic, vascular, and immune perturbations in adult Off-HFD mice, with marked sex-specific differences. Although both male and female Off-HFD mice developed progressive cardiac hypertrophy, male offspring exhibited a more severe phenotype characterized by hypertension, increased vascular stiffness, impaired cardiac function, and myocardial fibrosis. To identify potential mechanisms underlying these changes, we performed DNA methylation analysis in collected hearts of newly weaned and adult offspring. This analysis revealed extensive, sex-dependent alterations in DNA methylation within or nearby genes involved in cardiac development, lipid metabolism, hypertrophic growth, and inflammatory signaling. Importantly, many of these epigenetic alterations persisted into adulthood, suggesting that maternal obesity establishes a durable molecular memory in the offspring heart. Consistent with these findings, transcriptome analysis of adult hearts revealed activation of gene programs associated with heart failure and pathological cardiac remodeling in male Off-HFD mice, whereas female Off-HFD mice showed activation of pathways consistent with adaptive or cardioprotective responses. Together, these findings demonstrate that maternal high fat diet induces early-life epigenetic remodeling in the offspring heart that persists into adulthood and is associated with sex-specific metabolic, functional, vascular, and immune dysregulations. By linking early epigenomic changes to adult cardiac disease susceptibility, this study identifies potential developmental windows for preventive and early therapeutic interventions aimed at reducing cardiovascular risk in offspring exposed to maternal obesity in utero.

molecular biology↗

bioRxiv2024

Convergent genetic adaptation in human tumors developed under systemic hypoxia and in populations living at high altitudes

EPAS1HIF2 is the primary gene implicated in systemic hypoxia adaptation. Conversely, aberrantly activated EPAS1HIF2 acts as a tumor driver against which anti-tumor therapeutics are proven effective. We elucidated connections between adaptation to systemic hypoxia in high-altitude populations, such as Tibetans and Sherpas, and human tumors. Similar to the accelerated adaptability observed in high-altitude populations via genetic introgression, tumors from patients with hypoxia since birth exhibited impaired DNA repair and increased mutation burden. As in high-altitude dwellers, EPAS1HIF2 genetic variants were positively selected within sympathetic tumors developed under hypoxia, with a consistently high frequency of 90%. Bulk and single-cell RNA sequencing followed by in vitro studies have shown that hypoxia and EPAS1HIF2 gain-of-function tumor mutations induce COX4i2 expression and impair mitochondrial respiration, indicating that decreased cellular oxygen consumption may confer a proliferative advantage in hypoxia. Analyzing medical data from a patient cohort with hypoxia since birth who developed/did not develop tumors revealed tissue-specific and time-dependent tumorigenic effects of systemic hypoxia, which is limited to oxygen-sensitive and responsive cells, particularly during the postnatal period. This study supports connections between the EPAS1HIF2 genetic adaptation in human tumors developed under systemic hypoxia to populations living in high altitudes. The genetic adaptations in populations to different stressors can be explored further to understand tumorigenesis and tumor evolution.

cancer biology↗

bioRxiv2017

Dynein Pulling Forces On Ruptured Nuclei Counteract Lamin-Mediated Nuclear Envelope Repair Mechanisms In Vivo

Recent work done exclusively in tissue culture cells revealed that the nuclear envelope (NE) undergoes ruptures leading to transient mixing of nuclear and cytoplasmic components. The duration of transient NE ruptures depends on lamins, however the underlying mechanisms and the relevance to in vivo events is not known. Here, we use C. elegans embryos to show that dynein forces that position nuclei increase the severity of lamin-induced NE ruptures in vivo. In the absence of dynein forces, lamin prevents nuclear-cytoplasmic mixing caused by NE ruptures. By monitoring the dynamics of NE rupture events, we demonstrate that lamin is required for a distinct step in NE recovery that restricts nucleocytoplasmic mixing prior to the full restoration of NE rupture sites. We show that laser-induced puncture of the NE recapitulates phenotypes associated with NE recovery in wild type cells. Surprisingly, we find that embryonic lethality does not correlate with the incidence of NE rupture events suggesting that embryos survive transient losses of NE compartmentalization during early embryogenesis. In addition to presenting the first mechanistic analysis of transient NE ruptures in vivo, this work demonstrates that lamin controls the duration of NE ruptures by opposing dynein forces on ruptured nuclei to allow reestablishment of the NE permeability barrier and subsequent restoration of NE rupture sites.

developmental biology↗