Probability landscapes for integrative genomics

<p>Abstract</p> <p>Background</p> <p>The comprehension of the gene regulatory code in eukaryotes is one of the major challenges of systems biology, and is a requirement for the development of novel therapeutic strategies for multifactorial diseases. Its bi-fold degeneration precludes brute force and statistical approaches based on the genomic sequence alone. Rather, recursive integration of systematic, whole-genome experimental data with advanced statistical regulatory sequence predictions needs to be developed. Such experimental approaches as well as the prediction tools are only starting to become available and increasing numbers of genome sequences and empirical sequence annotations are under continual discovery-driven change. Furthermore, given the complexity of the question, a decade(s) long multi-laboratory effort needs to be envisioned. These constraints need to be considered in the creation of a framework that can pave a road to successful comprehension of the gene regulatory code.</p> <p>Results</p> <p>We introduce here a concept for such a framework, based entirely on systematic annotation in terms of probability profiles of genomic sequence using any type of relevant experimental and theoretical information and subsequent cross-correlation analysis in hypothesis-driven model building and testing.</p> <p>Conclusion</p> <p>Probability landscapes, which include as reference set the probabilistic representation of the genomic sequence, can be used efficiently to discover and analyze correlations amongst initially heterogeneous and un-relatable descriptions and genome-wide measurements. Furthermore, this structure is usable as a support for automatically generating and testing hypotheses for alternative gene regulatory grammars and the evaluation of those through statistical analysis of the high-dimensional correlations between genomic sequence, sequence annotations, and experimental data. Finally, this structure provides a concrete and tangible basis for attempting to formulate a mathematical description of gene regulation in eukaryotes on a genome-wide scale.</p

CDK2 and PKA Mediated-Sequential Phosphorylation Is Critical for p19INK4d Function in the DNA Damage Response

DNA damage triggers a phosphorylation-based signaling cascade known as the DNA damage response. p19INK4d, a member of the INK4 family of CDK4/6 inhibitors, has been reported to participate in the DNA damage response promoting DNA repair and cell survival. Here, we provide mechanistic insight into the activation mechanism of p19INK4d linked to the response to DNA damage. Results showed that p19INK4d becomes phosphorylated following UV radiation, β-amyloid peptide and cisplatin treatments. ATM-Chk2/ATR-Chk1 signaling pathways were found to be differentially involved in p19INK4d phosphorylation depending on the type of DNA damage. Two sequential phosphorylation events at serine 76 and threonine 141 were identified using p19INK4d single-point mutants in metabolic labeling assays with 32P-orthophosphate. CDK2 and PKA were found to participate in p19INK4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19INK4d induced by DNA damage was shown to be dependent on serine 76 phosphorylation. Most importantly, both phosphorylation sites were found to be crucial for p19INK4d function in DNA repair and cell survival. In contrast, serine 76 and threonine 141 were dispensable for CDK4/6 inhibition highlighting the independence of p19INK4d functions, in agreement with our previous findings. These results constitute the first description of the activation mechanism of p19INK4d in response to genotoxic stress and demonstrate the functional relevance of this activation following DNA damage

Association between Low Density Lipoprotein Receptor-Related Protein 2 Gene Polymorphisms and Bone Mineral Density Variation in Chinese Population

Low density lipoprotein receptor-related protein 2 gene (LRP2) is located next to the genomic region showing suggestive linkage with both hip and wrist bone mineral density (BMD) phenotypes. LRP2 knockout mice showed severe vitamin D deficiency and bone disease, indicating the involvement of LRP2 in the preservation of vitamin D metabolites and delivery of the precursor to the kidney for the generation of 1α,25(OH)2D3. In order to investigate the contribution of LRP2 gene polymorphisms to the variation of BMD in Chinese population, a total of 330 Chinese female-offspring nuclear families with 1088 individuals and 400 Chinese male-offspring nuclear families with 1215 individuals were genotyped at six tagSNPs of the LRP2 gene (rs2389557, rs2544381, rs7600336, rs10210408, rs2075252 and rs4667591). BMD values at the lumbar spine 1–4 (L1-4) and hip sites were measured by DXA. The association between LRP2 polymorphisms and BMD phenotypes was assessed by quantitative transmission disequilibrium tests (QTDTs) in female- and male-offspring nuclear families separately. In the female-offspring nuclear families, rs2075252 and haplotype GA of rs4667591 and rs2075252 were identified in the nominally significant total association with peak BMD at L1-4; however, no significant within-family association was found between peak BMD at the L1-4 and hip sites and six tagSNPs or haplotypes. In male-offspring nuclear families, neither the six tagSNPs nor the haplotypes was in total association or within-family association with the peak BMD variation at the L1-4 and hip sites by QTDT analysis. Our findings suggested that the polymorphisms of LRP2 gene is not a major factor that contributes to the peak BMD variation in Chinese population

Atopic dermatitis and vitamin D: facts and controversies

Patients with atopic dermatitis have genetically determined risk factors that affect the barrier function of the skin and immune responses that interact with environmental factors. Clinically, this results in an intensely pruriginous and inflamed skin that allows the penetration of irritants and allergens and predisposes patients to colonization and infection by microorganisms. Among the various etiological factors responsible for the increased prevalence of atopic diseases over the past few decades, the role of vitamin D has been emphasized. As the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, and vitamin D is involved in both processes, it is reasonable to expect that vitamin D's status could be associated with atopic dermatitis' risk or severity. Such association is suggested by epidemiological and experimental data. in this review, we will discuss the evidence for and against this controversial relationship, emphasizing the possible etiopathogenic mechanisms involved.Univ Brasilia UNB, Brasilia, DF, BrazilFed Dist Hlth State Dept SES DF, Brasilia, DF, BrazilUniv Brasilia HUB UNB, Brasilia Univ Hosp, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilSão Paulo Fed Univ UNIFESP, Brasilia, DF, BrazilWeb of Scienc