Biology subjects

Martin-Trujillo, A.

Publications and source records attributed to Martin-Trujillo, A..

4 recordsLinked to original sources

bioRxiv2025

Signaling induced biophysical disruption of repressed chromatin domains drives immune cell fate

Cell fate transitions require signal-induced chromatin derepression, yet mechanisms governing transitions from repressed to active chromatin states are poorly understood. We discover, at fate-defining genes across immune cell types, a signal-induced histone code, and describe domains of H3 serine 28 phosphorylation (H3S28ph) spanning architectural features, often coincident with repressive H3 lysine 27 trimethylation (H3K27me3). Employing biophysical, single cell, and functional approaches to study signal-induced cell differentiation in the immune system, we uncover epigenomic transitions and cell fate choices precipitated by histone phosphorylation (H3ph). Mechanistically, H3ph overrides Polycomb Repressive Complex 2 (PRC2) chromatin repression, biophysically disrupts polynucleosome compaction, and promotes loss of H3K27me3, while increasing activating H3K27 acetylation and H3K36 dimethylation to drive domain interactivity and stabilize transcription. We demonstrate the activity of H3ph in several cell fate transitions and illuminate biophysical mechanisms enabling rapid signal-activated chromatin derepression, processes with general relevance for cellular differentiation and activation.

immunology↗

bioRxiv2020

Pervasive cis effects of variation in copy number of large tandem repeats on local epigenetics and gene expression

Variable Number Tandem Repeats (VNTRs) are composed of large tandemly repeated motifs, many of which are highly polymorphic in copy number. However, due to their large size and repetitive nature, they remain poorly studied. To investigate the regulatory potential of VNTRs, we used read-depth data from Illumina whole genome sequencing to perform association analysis between copy number of ~70,000 VNTRs (motif size [≥]10bp) with both gene expression (404 samples in 48 tissues) and DNA methylation (235 samples in peripheral blood), identifying thousands of VNTRs that are associated with local gene expression (eVNTRs) and DNA methylation levels (mVNTRs). Using large-scale replication analysis in an independent cohort we validated 73-80% of signals observed in the two discovery cohorts, providing robust evidence to support that these represent genuine associations. Further, conditional analysis indicated that many eVNTRs and mVNTRs act as QTLs independently of other local variation. We also observed strong enrichments of eVNTRs and mVNTRs for regulatory features such as enhancers and promoters. Using the Human Genome Diversity Panel, we defined sets of VNTRs that show highly divergent copy numbers among human populations, show that these are enriched for regulatory effects on gene expression and epigenetics, and preferentially associate with genes that have been linked with human phenotypes through GWAS. Our study provides strong evidence supporting functional variation at thousands of VNTRs, and defines candidate sets of VNTRs, copy number variation of which potentially plays a role in numerous human phenotypes.

genomics↗

bioRxiv2020

A survey of rare epigenetic variation in 23,116 human genomes identifies disease-relevant epivariations and novel CGG expansions

There is growing recognition that epivariations, most often recognized as promoter hypermethylation events that lead to gene silencing, are associated with a number of human diseases. However, little information exists on the prevalence and distribution of rare epigenetic variation in the human population. In order to address this, we performed a survey of methylation profiles from 23,116 individuals using the Illumina 450k array. Using a robust outlier approach, we identified 4,452 unique autosomal epivariations, including potentially inactivating promoter methylation events at 384 genes linked to human disease. For example, we observed promoter hypermethylation of BRCA1 and LDLR at population frequencies of ~1 in 3,000 and ~1 in 6,000 respectively, suggesting that epivariations may underlie a fraction of human disease which would be missed by purely sequence-based approaches. Using expression data, we confirmed that many epivariations are associated with outlier gene expression. Analysis of SNV data and monozygous twin pairs suggests that approximately two thirds of epivariations segregate in the population secondary to underlying sequence mutations, while one third are likely sproradic events that occur post-zygotically. We identified 25 loci where rare hypermethylation coincided with the presence of an unstable CGG tandem repeat, and validated the presence of novel CGG expansions at several of these, identifying the molecular defect underlying most of the known folate-sensitive fragile sites in the genome. Our study provides a catalog of rare epigenetic changes in the human genome, gives insight into the underlying origins and consequences of epivariations, and identifies many novel hypermethylated CGG repeat expansions.

genomics↗

bioRxiv2018

Identification of rare de novo epigenetic variations in congenital disorders

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. With recent dramatic advances in genomic technologies, genome-wide surveys of cohorts of patients with ND/CAs for point mutations and structural variations have greatly advanced our understanding of their genetic etiologies1,2. However, even after whole genome sequencing (WGS), a substantial fraction of such disorders remain unexplained3. In contrast, the possibility that constitutive epigenetic variations (epivariations) might underlie such traits has not been well explored. We hypothesized that some cases of ND/CA are caused by aberrations of DNA methylation that lead to a dysregulation of normal genome function. By comparing DNA methylation profiles from 489 individuals with ND/CAs against 1,534 population controls, we identified epivariations as a frequent occurrence in the human genome. De novo epivariations were significantly enriched in cases when compared to controls. RNAseq data from population studies showed that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detected and replicated an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations. Thus, some epivariations occur secondary to cis-linked mutations in regulatory regions, providing a rationale for interpreting non-coding genetic variation. We propose that epivariations likely represent the causative genomic defect in 5-10% of patients with unexplained ND/CAs. This constitutes a yield comparable to CNV microarrays, and as such has significant diagnostic relevance.

genomics↗