RESUMEN
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
Asunto(s)
Envejecimiento , Cromatina , Factor de Transcripción AP-1 , Animales , Envejecimiento/genética , Envejecimiento/metabolismo , Factor de Transcripción AP-1/metabolismo , Cromatina/metabolismo , Ratones , Humanos , Ratones Endogámicos C57BL , Sitios de UniónRESUMEN
Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA's role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT.
Asunto(s)
Aurora Quinasa A , Quistes , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Animales , Ratones , Aurora Quinasa A/genética , Monoéster Fosfórico Hidrolasas , Enfermedades Renales Poliquísticas/genética , Enfermedades Renales Poliquísticas/prevención & control , Proteínas Proto-Oncogénicas c-akt/genéticaRESUMEN
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading cause of kidney failure and is associated with substantial morbidity and mortality. Interstitial inflammation is attributed to the action of infiltrating macrophages and is a feature thought to aggravate disease progression. Here, we investigated the therapeutic potential of the anti-inflammatory IL37b cytokine as a treatment for ADPKD using genetic mouse models, demonstrating that transgenic expression of human IL37b reduced collecting duct cyst burden in both early and adult-onset ADPKD rodent models. Moreover, injection of recombinant human IL37b could also reduce cyst burden in early onset ADPKD mice, an observation not associated with increased macrophage number at early stages of cyst formation. Interestingly, transgenic IL37b expression also did not alter macrophage numbers in advanced disease. Whole kidney RNA-seq highlighted an IL37b-mediated upregulation of the interferon signaling pathway and single-cell RNA-seq established that these changes originate at least partly from kidney resident macrophages. We further found that blocking type I interferon signaling in mice expressing IL37b resulted in increased cyst number, confirming this as an important pathway by which IL37b exerts its beneficial effects. Thus, our studies show that IL37b promotes interferon signaling in kidney resident macrophages which suppresses cyst initiation, identifying this protein as a potential therapy for ADPKD.
Asunto(s)
Quistes , Riñón Poliquístico Autosómico Dominante , Ratones , Humanos , Animales , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/genética , Inflamación/genética , Inflamación/complicaciones , Riñón/metabolismo , Quistes/complicaciones , Interleucinas , InterferonesRESUMEN
"BACKGROUND: It is estimated that 1%-2% of women develop cervical intraepithelial neoplasia grade 2-3 (CIN 2-3) annually worldwide. The prevalence among women living with HIV is higher, at 10%. If left untreated, CIN 2-3 can progress to cervical cancer. WHO has previously published guidelines for strategies to screen and treat precancerous cervical lesions and for treatment of histologically confirmed CIN 2-3. METHODS: Guidelines were developed using the WHO Handbook for Guideline Development and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. A multidisciplinary guideline panel was created. Systematic reviews of randomized controlled trials and observational studies were conducted. Evidence tables and Evidence to Recommendations Tables were prepared and presented to the panel. RESULTS: There are nine recommendations for screen-and-treat strategies to prevent cervical cancer, including the HPV test, cytology, and visual inspection with acetic acid. There are seven for treatment of CIN with cryotherapy, loop electrosurgical excision procedure, and cold knife conization. CONCLUSION: Recommendations have been produced on the basis of the best available evidence. However, high-quality evidence was not available. Such evidence is needed, in particular for screen-and-treat strategies that are relevant to low- and middle-income countries."