Biology subjects

San Martin, R.

Publications and source records attributed to San Martin, R..

9 recordsLinked to original sources

bioRxiv2026

Abnormal nuclear organization impairs adipogenic lineage commitment and terminal maturation in Hutchinson-Gilford progeria syndrome (HGPS)

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal premature aging disorder driven by progerin, a truncated Lamin A protein that destabilizes nuclear architecture and disproportionately affects mesenchymal-lineage tissues. One notable mesenchymal lineage defect in Progeria patients is early and severe subcutaneous lipodystrophy. We hypothesized that disorganized chromatin architecture underlies the failure of mesenchymal stem cell (MSC) lineage commitment and adipogenesis in HGPS. To test this while preserving donor age, epigenetic history, and tissue context, we induced adipogenesis in age-matched healthy and HGPS patient-derived dermal fibroblasts and profiled cells using imaging, bulk RNA-seq, and Hi-C across the differentiation time course. We found that HGPS fibroblasts commit to the adipogenic lineage at rates comparable to healthy controls but diverge downstream: induced cells display aberrant lipid-droplet morphology, mount a disorganized and delayed transcriptional response, and retain priming for alternative mesenchymal lineages (osteochondrogenic, vascular) alongside stalled adipogenic maturation. Hi-C revealed that HGPS fibroblasts exhibit some baseline spatial compartment differences from healthy cells, but more notably show differences in how they reorganize compartments during adipogenic induction. Compartment-transcription coupling was strong during adipogenesis for lipid-metabolic genes in healthy cells but was more dysregulated in HGPS. These results indicate that HGPS disrupts lineage consolidation rather than initiation, associated with disease-specific failures in chromatin reorganization during differentiation.

cell biology↗

bioRxiv2024

Rearrangement of 3D genome organization in breast cancer epithelial - mesenchymal transition and metastasis organotropism

Breast cancer cells exhibit organotropism during metastasis, showing preferential homing to certain organs such as bone, lung, liver, and brain. One potential explanation for this organotropic behavior is that cancer cells gain properties that enable thriving in certain microenvironments. Such specific metastatic traits may arise from gene regulation at the primary tumor site. Spatial genome organization plays a crucial role in oncogenic transformation and progression, but the extent to which chromosome architecture contributes to organ-specific metastatic traits is unclear. This work characterizes chromosome architecture changes associated with organotropic metastatic traits. By comparing a collection of genomic data from different subtypes of localized and lung metastatic breast cancer cells with both normal and cancerous lung cells, we find important trends of genomic reorganization. The most striking differences in 3D genome compartments segregate cell types according to their epithelial vs. mesenchymal status. This EMT compartment signature occurs at genomic regions distinct from transcription-defined EMT signatures, suggesting a separate layer of regulation. Specifically querying organotropism, we find 3D genome changes consistent with adaptations needed to survive in a new microenvironment, with lung metastatic breast cells exhibiting compartment switch signatures that shift the genome architecture to a lung cell-like conformation and brain metastatic prostate cancer cells showing compartment shifts toward a brain-like state. TCGA patient data reveals gene expression changes concordant with these organ-permissive compartment changes. These results suggest that genome architecture provides an additional level of cell fate specification informing organotropism and enabling survival at the metastatic site. SIGNIFICANCEComputational analysis of a cohort of cancer cell lines reveals some 3D genome spatial compartment changes are associated with transitions in cancer cell state that relate to metastasis (EMT) and others reflect the characteristics of the metastatic organ context.

cancer biology↗

bioRxiv2023

Amorphous calcium phosphate-coated surfaces as a model for bone microenvironment in prostate cancer

Bone metastasis remains one of the biggest challenges in the treatment of prostate cancer, and other solid tumors such as breast, lung, and colon. Modeling a complex microenvironment in-vitro, such as the bone niche, requires interrogation of cell-cell interactions, specific extracellular matrix proteins and a high calcium environment. Here, we present a fast and cost-effective system in which commercially available, non-adhesive, cell culture vessels are coated with amorphous calcium phosphate (ACP) as a surrogate for bone matrix. We further present modified protocols for subculturing cells, as well as nucleic acid and protein collection in high calcium samples. We find that prostate epithelial cell lines show increased adhesion and proliferation when cultured in these surfaces, as well as independence from androgen starvation. We observe gene expression changes on ACP surfaces in early adenocarcinoma cell lines which may reflect alterations relevant to prostate cancer progression. Summary statementTo model the role of calcium in the microenvironment of the metastatic bone niche, we developed a cost-effective way to coat cell culture vessels in bioavailable calcium, and show that it has an effect on prostate cancer cell survival

cancer biology↗

bioRxiv2022

Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation

Interactions of chromatin with the nuclear lamina play a significant role in properly organizing the genome in 3D space and in regulating gene expression. Genome wide studies have inferred the global association between the lamina, heterochromatin, gene repression and the B genomic compartment, and repositioning genes to the lamina can result in their repression. However, there are scenarios in which these features are discordant and, in those cases, the relative contribution to gene regulation of genomic compartment, chromatin, and lamin association status can be examined. Here we compared datasets from cell lines representing different states of differentiation across different cell type lineages to examine the relationships between changes in genomic compartmentalization, lamin association, and gene expression. With these data, we could examine, for example, what gene expression changes occur when a B compartment region is moved from the nuclear interior to the nuclear lamina and what differences exist between lamin associated and internal A compartment regions. In general, we observed an additive rather than redundant effect in which lamin association and compartment status both contribute to gene expression state. However, we found that cell type lineages differed in whether compartment status or lamin association had a dominant influence on gene expression. Finally, we identified conserved trends of how compartment and lamin association status influence the likelihood that gene expression will be induced or repressed in response to a physiochemical treatment.

genomics↗

bioRxiv2022

Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification.

Hutchinson-Gilford Progeria Syndrome results from a mutation in Lamin A, and it is characterized by the incorporation of progerin into the nuclear lamina. Progerin expression leads to alterations in genome architecture, nuclear morphology, and epigenetic states, which in turn cause altered phenotypes in all cells of the mesenchymal lineage. Here, we report a comprehensive analysis of the transcriptional status of patient derived HGPS fibroblasts, including nine cell lines not previously reported. We observe that these fibroblasts carry abnormal transcriptional signatures, centering around five main functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth. Stratification of patients by age revealed that a cohort of genes related to endochondral ossification and chondrogenic commitment show altered expression patterns in children aged four to seven years old, where this differentiation program starts in earnest, related to the growth of long bones. We further report changes in lamin associated domains and 3D genome organization around a cohort of genes of interest, identified in this study.

genomics↗

bioRxiv2021

Alterations in chromosome spatial compartmentalization classify prostate cancer progression

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression, genomic aberrations, and cellular morphology. These processes are in turn dependent in part on the 3D structure of chromosomes, packaged inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, ranging from normal epithelium to bone metastasis. Here, we describe how chromatin compartmentalization identity (A-open vs. B-closed) changes with progression: specifically, we find that 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches could prelude transcription activation and are accompanied by changes in the structure, size, and boundaries of the topologically associating domains (TADs). Further, compartmentalization changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation: one of the main drivers of prostate cancer. These results suggest that discrete, 3D genome structure changes play a deleterious role in prostate cancer progression. SummaryThrough a systematic analysis of chromosome conformation capture in a cohort of cells that model cancer progression, San Martin et.al. find that rearrangement of the 3D genome structure in prostate cancer is a potential mechanism for disease exacerbation and that genome-wide compartment identity can classify cancer according to progression.

cancer biology↗

bioRxiv2019

Constricted migration contributes to persistent 3D genome structure changes associated with an invasive phenotype in melanoma cells

To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation and DNA repair, here we investigate the relationship between 3D genome structure and constricted migration in cancer cells. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone multiple rounds of constricted migration. These cells display a stably higher migration efficiency, elongated morphology, and differences in the distribution of Lamin A/C and heterochromatin. Hi-C experiments reveal differences in chromosome spatial compartmentalization specific to cells that have passed through constrictions and related alterations in expression of genes associated with migration and metastasis. Certain features of the 3D genome structure changes, such as a loss of B compartment interaction strength, are consistently observed after constricted migration in clonal populations of A375 cells and in MDA-MB-231 breast cancer cells. Our observations suggest that consistent types of chromosome structure changes are induced or selected by passage through constrictions and that these may epigenetically encode stable differences in gene expression and cellular migration phenotype.

systems biology↗

bioRxiv2019

Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization

The three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. Fibroblasts, lymphoblasts, and ATM-deficient fibroblasts were irradiated with 5 Gy X-rays and Hi-C was performed after 30 minutes, 24 hours, or 5 days after irradiation. 3D genome changes after irradiation were cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibited an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation was not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.

genomics↗

bioRxiv2017

The role of stimulus similarity on the summation effect in human causal learning

Several contemporary models of associative learning anticipate that the higher responding to a compound of two cues separately trained with a common outcome than to each of the cues alone -a summation effect-is modulated by the similarity between the cues forming the compound. Here, we explored this hypothesis in a series of causal learning experiments with humans. Participants were presented with two visual cues that separately predicted a common outcome and later asked for the outcome predicted by the compound of the two cues. Importantly, the cues similarity was varied between groups through changes in shape, spatial position, color, configuration and rotation. In variance with the predictions of these models, we observed similar and strong levels of summation in both groups across all manipulations of similarity (Experiments 1-5). The summation effect was significantly reduced by manipulations intended to impact assumptions about the causal independence of the cues forming the compound, but this reduction was independent of stimulus similarity (Experiment 6). These results are problematic for similarity-based models and can be more readily explained by rational approaches to causal learning.

animal behavior and cognition↗