Francisco Bustos

Epigenetic Signatures at the RUNX2-P1 and Sp7 Gene Promoters Control Osteogenic Lineage Commitment of Umbilical Cord-Derived Mesenchymal Stem Cells.

Whartons Jelly mesenchymal stem cells (WJ‐MSCs) are an attractive potential source of multipotent stem cells for bone tissue replacement therapies. However, the molecular mechanisms involved in their osteogenic conversion are poorly understood. Particularly, epigenetic control operating at the promoter regions of the two master regulators of the osteogenic program, RUNX2/P57 and SP7 has not yet been described in WJ‐MSCs. Via quantitative PCR profiling and chromatin immunoprecipitation (ChIP) studies, here we analyze the ability of WJ‐MSCs to engage osteoblast lineage. In undifferentiated WJ‐MSCs, RUNX2/P57 P1, and SP7 promoters are found deprived of significant levels of the histone post‐translational marks that are normally associated with transcriptionally active genes (H3ac, H3K27ac, and H3K4me3). Moreover, the RUNX2 P1 promoter lacks two relevant histone repressive marks (H3K9me3 and H3K27me3). Importantly, RUNX2 P1 promoter is found highly enriched in the H3K4me1 mark, which has been shown recently to mediate gene repression of key regulatory genes. Upon induction of WJ‐MSCs osteogenic differentiation, we found that RUNX2/P57, but not SP7 gene expression is strongly activated, in a process that is accompanied by enrichment of activating histone marks (H3K4me3, H3ac, and H3K27ac) at the P1 promoter region. Histone mark analysis showed that SP7 gene promoter is robustly enriched in epigenetic repressive marks that may explain its poor transcriptional response to osteoblast differentiating media. Together, these results point to critical regulatory steps during epigenetic control of WJ‐MSCs osteogenic lineage commitment that are relevant for future applications in regenerative medicine. J. Cell. Physiol. 232: 2519–2527, 2017.

Leveraging Social Network Analysis with Topic Models and the Semantic Web

Social Network Analysis (SNA) and Web Mining (WM) techniques are being applied to study the structures of social networks in order to manage their dynamics and predict their evolution. This paper describes how we used Semantically-Interlinked Online Communities (SIOC) ontology to represent the (latent) semantic relationships between the members of a large community forum (about 2,500), Plexilandia. We extended SIOC, taking advantage of topic-based text mining and developed data mining algorithms that used our SIOC extensions to provide a better understanding of the social dynamics of the members of the Plexilandia community. This new understanding helped us to detect and discover the key members of Plexilandia successfuly.

Runt‐Related Transcription Factor 2 Induction During Differentiation of Wharton's Jelly Mesenchymal Stem Cells to Osteoblasts Is Regulated by Jumonji AT‐Rich Interactive Domain 1B Histone Demethylase

Novel bone regeneration approaches aim to obtain immature osteoblasts from somatic stem cells. Umbilical cord Whartons jelly mesenchymal stem cells (WJ‐MSCs) are an ideal source for cell therapy. Hence, the study of mechanisms involved in WJ‐MSC osteoblastic differentiation is crucial to exploit their developmental capacity. Here, we have assessed epigenetic control of the Runt‐related transcription factor 2 (RUNX2) osteogenic master regulator gene in WJ‐MSC. We present evidence indicating that modulation of RUNX2 expression through preventing Jumonji AT‐rich interactive domain 1B (JARID1B) histone demethylase activity is relevant to enhance WJ‐MSC osteoblastic potential. Hence, JARID1B loss of function in WJ‐MSC results in increased RUNX2/p57 expression. Our data highlight JARID1B activity as a novel target to modulate WJ‐MSC osteoblastic differentiation with potential applications in bone tissue engineering. Stem Cells 2017;35:2430–2441

RUNX2 Induction during Differentiation of Wharton's Jelly Mesenchymal Stem Cells to Osteoblasts is Regulated by JARID1B Histone Demethylase

Novel bone regeneration approaches aim to obtain immature osteoblasts from somatic stem cells. Umbilical cord Whartons jelly mesenchymal stem cells (WJ‐MSCs) are an ideal source for cell therapy. Hence, the study of mechanisms involved in WJ‐MSC osteoblastic differentiation is crucial to exploit their developmental capacity. Here, we have assessed epigenetic control of the Runt‐related transcription factor 2 (RUNX2) osteogenic master regulator gene in WJ‐MSC. We present evidence indicating that modulation of RUNX2 expression through preventing Jumonji AT‐rich interactive domain 1B (JARID1B) histone demethylase activity is relevant to enhance WJ‐MSC osteoblastic potential. Hence, JARID1B loss of function in WJ‐MSC results in increased RUNX2/p57 expression. Our data highlight JARID1B activity as a novel target to modulate WJ‐MSC osteoblastic differentiation with potential applications in bone tissue engineering. Stem Cells 2017;35:2430–2441

Protein Kinases in Pluripotency—Beyond the Usual Suspects

Post-translational modification of proteins by phosphorylation plays a key role in regulating all aspects of eukaryotic biology. Embryonic stem cell (ESC) pluripotency, defined as the ability to differentiate into all cell types in the adult body, is no exception. Maintenance and dissolution of pluripotency are tightly controlled by phosphorylation. As a result, key signalling pathways that regulate pluripotency have been identified and their functions well characterised. Amongst the best studied are the fibroblast growth factor (FGF)-ERK1/2 pathway, PI3K-AKT, the leukemia inhibitory factor (LIF)-JAK-STAT3 axis, Wnt-GSK3 signalling, and the transforming growth factor (TGF)β family. However, these kinase pathways constitute only a small proportion of the protein kinase complement of pluripotent cells, and there is accumulating evidence that diverse phosphorylation systems modulate ESC pluripotency. Here, we review recent progress in understanding the overarching role of phosphorylation in mediating communication from the cellular environment, metabolism, and cell cycle to the core pluripotency machinery.

Leveraging social network analysis with topic models and the Semantic Web extended

Research in the Semantic Web, especially in modeling virtual communities, has provided models useful to represent the richness of these social network interactions. The SIOC Semantically-Interlinked Online Communities vocabulary provides concepts and properties that can be used to describe information from online communities e.g., message boards, wikis, weblogs, etc.. However, the SIOC ontology does not consider social aspects nor the higher order semantics hidden in linkages between community members. This paper describes SIOC-SNA-DM, an extension of the SIOC vocabulary. SIOC-SNA-DMs model is tri-partite, consisting of People, Policies, and Purposes which are social aspects observable in most social communities. A challenge to using our model is how to populate these aspects, since higher order semantics from interactions need to be extracted. Thus, we explain how this population is done with advanced text mining using a latent semantic technique over a large virtual community called Plexilandia.cl with more than 2500 musicians working on the site.Our previous work, in this area, has shown how including these social aspects help to outperform results generated by state-of-the-art techniques. One of the novelties of this present work is the introduction and the elucidation of SIOC-SNA-DM, and how to populate the ontology in order to support the social aspects needed to enhance results of Social Network Mining techniques.

RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation

Summary X-linked intellectual disability (XLID) is a heterogeneous syndrome affecting mainly males. Human genetics has identified >100 XLID genes, although the molecular and developmental mechanisms underpinning this disorder remain unclear. Here, we employ an embryonic stem cell model to explore developmental functions of a recently identified XLID gene, the RNF12/RLIM E3 ubiquitin ligase. We show that RNF12 catalytic activity is required for proper stem cell maintenance and neural differentiation, and this is disrupted by patient-associated XLID mutation. We further demonstrate that RNF12 XLID mutations specifically impair ubiquitylation of developmentally relevant substrates. XLID mutants disrupt distinct RNF12 functional modules by either inactivating the catalytic RING domain or interfering with a distal regulatory region required for efficient ubiquitin transfer. Our data thereby uncover a key function for RNF12 E3 ubiquitin ligase activity in stem cell and neural development and identify mechanisms by which this is disrupted in intellectual disability.

El derecho a la prueba y la prueba ilícita en el derecho internacional de los derechos humanos

Las normas de exclusion probatoria que se han introducido desde la Reforma Procesal Penal chilena, plantean diversos problemas al ser extrapoladas a cuestiones no criminales. Esta ponencia se propone, desde esta perspectiva, analizar los principales Tratados Internacionales de proteccion de los Derechos Humanos, para determinar la amplitud del derecho a la prueba, y especialmente las limitaciones que dicen relacion con la exclusion de pruebas por ilicitud en el Derecho Internacional de los Derechos Humanos.