DNA methylation and specific sequience motifs: association with genetics instability in p53 in cancer, and other loci in degenerative disorders and aging

Analysis of the p53 somatic mutation database reveals that genetic instability is strongly associated with methylation and repeated sequences which contribute to the formation of alternative DNA conformations. Similar genetic instability is observed in neurological disorders and aging. In the present analysis we identified common sequence elements associated with genetic instability in the above disorders. The formation of new epigenetic/genotoxic modification sites, like CC, GG, CpG, CCC and GGG sites due to AT>GC transitions and AT>CG transversions, next to TG and CA sequences can induce p53 mutations, whereas genetic instability at repeated sequences, such as CGG and CTG, in association with CpG methylation and other specific sequence elements like TG, consist the basis of various neurological disorders. Previous reports have also shown that in aging tissues, GT/TG, CA/AC sequences as well as DNA repeats and methylation are common motifs, whereas CA microsatellites can cause DNA conformational changes. These common sequence elements probably represent universal sites related to genetic instability in various genes including cancer related p53, development of various neurological diseases and organ -specific genome deterioration and dysfunction at old age

In silico structural analysis of sequences containing 5-hydroxymethylcytosine reveals its potential as binding regulator for development, ageing and cancer-related transcription factors

The presence of 5-hydroxymethyl cytosine in DNA has been previously associated with ageing. Using in silico analysis of normal liver samples we presently observed that in 5-hydroxymethyl cytosine sequences, DNA methylation is dependent on the co-presence of G-quadruplexes and palindromes. This association exhibits discrete patterns depending on G-quadruplex and palindrome densities. DNase-Seq data show that 5-hydroxymethyl cytosine sequences are common among liver nucleosomes (p < 2.2x10−16) and threefold more frequent than nucleosome sequences. Nucleosomes lacking palindromes and potential G-quadruplexes are rare in vivo (1%) and nucleosome occupancy potential decreases with increasing G-quadruplexes. Palindrome distribution is similar to that previously reported in nucleosomes. In low and mixed complexity sequences 5-hydroxymethyl cytosine is frequently located next to three elements: G-quadruplexes or imperfect G-quadruplexes with CpGs, or unstable hairpin loops (TCCCAY6TGGGA) mostly located in antisense strands or finally A-/T-rich segments near these motifs. The high frequencies and selective distribution of pentamer sequences (including TCCCA, TGGGA) probably indicate the positive contribution of 5-hydroxymethyl cytosine to stabilize the formation of structures unstable in the absence of this cytosine modification. Common motifs identified in all total 5-hydroxymethyl cytosine-containing sequences exhibit high homology to recognition sites of several transcription factor families: homeobox, factors involved in growth, mortality/ageing, cancer, neuronal function, vision, and reproduction. We conclude that cytosine hydroxymethylation could play a role in the recognition of sequences with G-quadruplexes/palindromes by forming epigenetically regulated DNA ‘springs’ and governing expansions or compressions recognized by different transcription factors or stabilizing nucleosomes. The balance of these epigenetic elements is lost in hepatocellular carcinoma

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

Horvath’s epigenetic clock consists of 353 CpGs whose methylation levels can accurately predict the age of individuals. Using bioinformatics analysis, we investigated the conformation, energy characteristics and presence of tentative splice sites of the sequences surrounding the epigenetic clock CpGs, in relation to the median methylation changes in different ages, the presence of CpG islands and their position in genes. Common characteristics in the 100 nt sequences surrounding the epigenetic clock CpGs are G-quadruplexes and/or tentative splice site motifs. Median methylation increases significantly in sequences which adopt less stable structures during transcription. Methylation is higher when CpGs overlap with G-quadruplexes than when they precede them. Median methylation in epigenetic clock CpGs is higher in sequences expressed as single products rather than in multiple products and those containing single donors and multiple acceptors. Age-related methylation variation is significant in sequences without G-quadruplexes, particularly those producing low stability nascent RNA and those with splice sites. CpGs in sequences close to transcription start sites and those which are possibly never expressed (hypothetical proteins) undergo similar extent of age-related median methylation decrease and increase. Preservation of methylation is observed in CpG islands without G-quadruplexes, contrary to CpGs far from CpG islands (open sea). Sequences containing G-quadruplexes and RNA pseudoknots, determining the recognition by H3K27 histone methyltransferase, are hypomethylated. The presented structural DNA and co-transcriptional RNA analysis of epigenetic clock sequences, foreshadows the association of age-related methylation changes with the principle biological processes of DNA and histone methylation, splicing and chromatin silencing

Increased Δ133p53 mRNA in lung carcinoma corresponds with reduction of p21 expression

La “intervención social” no es sinónimo de Trabajo Social y tampoco refiere exclusivamente a “procedimientos”. En el campo académico resulta complejo reconocer a la “intervención social” como campo de conocimientos al igual que los conocimientos políticos o sociológicos, pero nos proponemos fundamentar en este texto que la Intervención Social sí constituye una categoría teórica en cuya definición ha aportado y aporta el Trabajo Social, pero también la Ciencia Política y la Sociología. En términos generales, podemos decir que la intervención social es un concepto que abarca el conjunto de procesos y estrategias que tienen lugar en la implementación-gestión de políticas sociales y en las múltiples formas de acción colectiva que desarrollan los sujetos en torno al acceso a derechos. Así planteado, estamos reconociendo un campo de conocimientos que incluye al Estado como garante de derechos y regulador en los procesos de redistribución democrática de los recursos en las sociedades desiguales en las que vivimos, al igual que a la sociedad movilizada en torno a demandas, necesidades y reivindicaciones en la conquista de esos derechos, en la reformulación de políticas y en los modos de acceso - o no acceso - a los mismos.“Social intervention” is not synonymous with Social Work and does not refer exclusively to “procedures.” In the academic field it is complex to recognize “social intervention” as a field of knowledge as well as political or sociological knowledge, but we propose to base in this text that Social Intervention does constitute a theoretical category in whose definition it has contributed and provides the Social Work, but also Political Science and Sociology. In general terms, we can say that social intervention is a concept that encompasses the set of processes and strategies that take place in the implementation-management of social policies and in the multiple forms of collective action that subjects develop around access to rights . Thus raised, we are recognizing a field of knowledge that includes the State as guarantor of rights and regulator in the processes of democratic redistribution of resources in the unequal societies in which we live, as well as to the society mobilized around demands, needs and claims in the conquest of those rights, in the reformulation of policies and in the modes of access - or non-access - to them.Facultad de Trabajo Socia