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Aldonza, M. B. D.

Publications and source records attributed to Aldonza, M. B. D..

2 recordsLinked to original sources

Integrative mapping of the dog epigenome: reference annotation for comparative inter-tissue and cross-species studies

The domestic dog has become a valuable model in exploring multifaceted diseases and biology important for human health. Large-scale dog genome projects produced high-quality draft references but still lack comprehensive annotation of encoded functional elements. Through the integrative next generation sequencing of transcriptomes paired with histone marks and DNA methylome profiling of 11 adult tissue types, implemented in a cross-species approach, we generated a reference epigenome of a domesticated dog. Using genome orthologues and synthenies, we deciphered the dogs epigenetic code by defining distinct chromatin states, allowing for genome-wide, integratable data production. We then characterized somatic super-enhancer landscapes and showed that genes mapped on these regions are associated with a broad range of biological and disease traits and are traceable to their tissue-of-origin. Ultimately, we delineated conserved epigenomic changes at the tissue- and species-specific resolutions. Our study provides an epigenomic blueprint of the dog for comparative biology and medical research.

genomics↗

Widespread multi-targeted therapy resistance via drug-induced secretome fucosylation

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post-translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy-induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.

cancer biology↗