Biology subjects

Martin, A. J. M.

Publications and source records attributed to Martin, A. J. M..

4 recordsLinked to original sources

bioRxiv2023

Transcriptional and Histone acetylation changes associated with CRE elements expose key factors governing the regulatory circuit in early stage of Huntington's disease models.

Huntingtons disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. Analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD, a starting point for early onset indicators of the progression of this disease.

genomics↗

bioRxiv2023

Random Forest approach for the identification of relationships between epigenetic marks and its application to robust assignment of chromatin states

Structural changes of chromatin modulate access to DNA for all proteins involved in transcription. These changes are linked to variations in epigenetic marks that allow to classify chromatin in different functional states depending on the pattern of these marks. Importantly, alterations in chromatin states are known to be linked with various diseases. For example, there are abnormalities in epigenetic patterns in different types of cancer. For most of these diseases, there is not enough epigenomic data available to accurately determine chromatin states for the cells affected in each of them, mainly due to high costs of performing this type of experiments but also because of lack of a sufficient amount of sample or degradation thereof. In this work we describe a cascade method based on a random forest algorithm to infer epigenetic marks, and by doing so, to reduce the number of experimentally determined marks required to assign chromatin states. Our approach identified several relationships between patterns of different marks, which strengthens the evidence in favor of a redundant epigenetic code.

genomics↗

bioRxiv2021

Comparative and systems analyses of Leishmania spp. non-coding RNAs through developmental stages

Leishmania spp. is the etiological agent of leishmaniases, neglected diseases that seek to be eradicated in the coming years. The life cycle of these parasites involve different host and stress environments. In recent years, many studies have shown that several protein coding genes are directly involved with the development and host interactions, however, little is still known about the role of ncRNAs in life cycle progression. In this study, we aimed to identify the genomic structure and function of ncRNAs from Leishmania spp. and to get insights into the RNAome of this protozoan genus. We studied 26 strains corresponding to 16 different species of Leishmania. Our RNAome analysis revealed the presence of several ncRNAs that are shared through different species, allowing us to differentiate between subgenus as well as species that are canonically related to visceral leishmaniasis. We also studied co-expression relationships between coding genes and ncRNAs which in the amastigote developmental stage for Leishmania braziliensis and L. donovani revealed the presence of miRNA-like co-expressed with several coding genes involved in starvation, survival and histone modification. This work constitutes the first effort to characterize the Leishmania RNAome, supporting further approaches to better understand the role of ncRNAs in the gene regulation, infective process and host-parasite interaction.

genomics↗

bioRxiv2020

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

Alteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinsons and Huntingtons disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

neuroscience↗