RT signatures of premature aging
RT signatures of premature aging
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Replication timing is a highly stable genomic property, is cell type-specific and highly conserved but altered in disease. In our lab, we exploit genome-wide RT characterization to identify disease abnormalities.
Particularly, we are interested in a family of rare genetic disorders colectively known as premature aging diseases. The most studied is Hutchinson-Gilford Progeria Syndrome (HGPS) caused by a point mutation in a component of the nuclear lamina. However, this family of diseases also includes many other syndromes that disrupt DNA repair, such as Werner, Rothmund-Thomson, Xeroderma Pigmentosum and Fanconi Anemia syndromes. Despite identification of causal mutations, there is no cure and children continue to die prematurely.
We identified a RT signature of premature aging syndromes. The premature aging-specific RT signature identified genomic regions that replicate late in normal cells derived from healthy donors of distinct ages but change to early replication in the disease. Work in our laboratoy is aimed to understand the developmental alterations in premature aging and its links to natural aging.
Nuclear alterations in HGPS cells. A) Analysis of primary cells from premature aging patients and healthy donors. B) Immunodetection of Lamin-B1 and γ-H2AX shows altered nuclear morphology and increased DNA damage (γ-H2AX foci) in HGPS cells. C) Unsupervised clustering analysis of RT-variable regions identified a specific RT signature of premature syndromes. D) Model of nuclear alterations in HGPS. Progerin expression (caused by LMNA mutation) induce nuclear blebbing, altered genome architecture, DNA damage (DSB) and senescence. Rivera-Mulia, et al., 2017.
RT alterations in pediatric leukemia
RT alterations in pediatric leukemia
The most common type of childhood cancer is acute lymphoblastic leukemia from B-cell lineage (B-ALL). Althoug distinct chromosomal abnormalities have been identified linked to specific types of B-ALL the causes remain poorly understood.
In this work, we exploited our RT signatures identification method to identify alterations in patients with pediatric leukemia.
We detected RT alterations associated with specific subtypes of B-ALL. Moreover, we performed a comparative analysis of RT programs of multiple B-ALL patients and distinct stages of B-cell development. Our findings suggest that B-ALL originates at specific stages of B-cell differentiation.
RT alterations in pediatric B-ALL. Pediatric B-ALL patient samples were procesed directly or after expansion in xenografts (PDX) for RT analysis. We developed optimized methods for RT analysis of limited samples (Early/Late and S/G1 cell fractions analyzed by Repli-Chip, Repli-seq, Repli-Capture-seq). We identified RT alterations that include the ROR1 gene in a specific subtype of B-ALL. These alterations distinguish B-ALL patient cells from normal B-cells and resemble a late stage of B-cell progenitors. Rivera-Mulia, et al., 2019.
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