Ethical and scientific aspects of human embryonic material research: The Great Britain regulations

We analyze the ethical and scientific issues of human embryonic specimen and its utilization for research purposes. Human embryonic specimens are the source of stem cells which are the foundation for all organs and tissue formation. The analysis of human embryonic specimens promises to obtain the essential knowledge about human development and reveal the causes of human development pathology. Ethical and scientific problems of human embryonic specimens donation and research are debated here. We review the impact that human embryonic specimens impose on scientific research, usage restrictions, risk assessment, research personnel and donor protection in view of the British, and other European publications, case reports, legislation, regulations and guidelines. This work is focused on the discussion of different aspects of donation and usage of human embryonic specimens obtained after the elective medical termination of pregnancy. We discuss suggestions for improvement of the ethical and scientific regulations for the work with human embryonic donor material in Russian Federation

Multiple Histone Methyl and Acetyltransferase Complex Components Bind the HLA-DRA Gene

Major histocompatibility complex class II (MHC-II) genes are fundamental components that contribute to adaptive immune responses. While characterization of the chromatin features at the core promoter region of these genes has been studied, the scope of histone modifications and the modifying factors responsible for activation of these genes are less well defined. Using the MHC-II gene HLA-DRA as a model, the extent and distribution of major histone modifications associated with active expression were defined in interferon-γ induced epithelial cells, B cells, and B-cell mutants for MHC-II expression. With active transcription, nucleosome density around the proximal regulatory region was diminished and histone acetylation and methylation modifications were distributed throughout the gene in distinct patterns that were dependent on the modification examined. Irrespective of the location, the majority of these modifications were dependent on the binding of either the X-box binding factor RFX or the class II transactivator (CIITA) to the proximal regulatory region. Importantly, once established, the modifications were stable through multiple cell divisions after the activating stimulus was removed, suggesting that activation of this system resulted in an epigenetic state. A dual crosslinking chromatin immunoprecipitation method was used to detect histone modifying protein components that interacted across the gene. Components of the MLL methyltransferase and GCN5 acetyltransferase complexes were identified. Some MLL complex components were found to be CIITA independent, including MLL1, ASH2L and RbBP5. Likewise, GCN5 containing acetyltransferase complex components belonging to the ATAC and STAGA complexes were also identified. These results suggest that multiple complexes are either used or are assembled as the gene is activated for expression. Together the results define and illustrate a complex network of histone modifying proteins and multisubunit complexes participating in MHC-II transcription

Identification of CIITA Regulated Genetic Module Dedicated for Antigen Presentation

The class II trans-activator CIITA is a transcriptional co-activator required for the expression of Major Histocompatibility Complex (MHC) genes. Although the latter function is well established, the global target-gene specificity of CIITA had not been defined. We therefore generated a comprehensive list of its target genes by performing genome-wide scans employing four different approaches designed to identify promoters that are occupied by CIITA in two key antigen presenting cells, B cells and dendritic cells. Surprisingly, in addition to MHC genes, only nine new targets were identified and validated by extensive functional and expression analysis. Seven of these genes are known or likely to function in processes contributing to MHC-mediated antigen presentation. The remaining two are of unknown function. CIITA is thus uniquely dedicated for genes implicated in antigen presentation. The finding that CIITA regulates such a highly focused gene expression module sets it apart from all other transcription factors, for which large-scale binding-site mapping has indicated that they exert pleiotropic functions and regulate large numbers of genes

Dysregulated Recruitment of the Histone Methyltransferase EZH2 to the Class II Transactivator (CIITA) Promoter IV in Breast Cancer Cells

One mechanism frequently utilized by tumor cells to escape immune system recognition and elimination is suppression of cell surface expression of Major Histocompatibility Class II (MHC II) molecules. Expression of MHC II is regulated primarily at the level of transcription by the Class II Transactivator, CIITA, and decreased CIITA expression is observed in multiple tumor types. We investigate here contributions of epigenetic modifications to transcriptional silencing of CIITA in variants of the human breast cancer cell line MDA MB 435. Significant increases in histone H3 lysine 27 trimethylation upon IFN-γ stimulation correlate with reductions in transcription factor recruitment to the interferon-γ inducible CIITA promoter, CIITApIV, and with significantly increased CIITApIV occupancy by the histone methyltransferase enhancer of zeste homolog 2 (EZH2). Most compelling is evidence that decreased expression of EZH2 in MDA MB 435 variants results in significant increases in CIITA and HLA-DRA mRNA expression, even in the absence of interferon-γ stimulation, as well as increased cell surface expression of MHC II. Together, these data add mechanistic insight to prior observations of increased EZH2 expression and decreased CIITA expression in multiple tumor types

Can blood-circulating factors unveil and delay your biological aging?

According to the World Health Organization, the population of over 60 will double in the next 30 years in the developed countries, which will enforce a further raise of the retirement age and increase the burden on the healthcare system. Therefore, there is an acute issue of maintaining health and prolonging active working longevity, as well as implementation of early monitoring and prevention of premature aging and age-related disorders to avoid early disability. Traditional indicators of biological age are not always informative and often require extensive and expensive analysis. The study of blood factors is a simple and easily accessible way to assess individual health and supplement the traditional indicators of a person’s biological age with new objective criteria. With age, the processes of growth and development, tissue regeneration and repair decline; they are gradually replaced by enhanced catabolism, inflammatory cell activity, and insulin resistance. The number of senescent cells supporting the inflammatory loop rises; cellular clearance by autophagy and mitophagy slows down, resulting in mitochondrial and cellular damage and dysfunction. Monitoring of circulated blood factors not only reflects these processes, but also allows suggesting medical intervention to prevent or decelerate the development of age-related diseases. We review the age-related blood factors discussed in recent publications, as well as approaches to slowing aging for healthy and active longevity. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Comparative Dynamics of Individual Ageing Among the Investigative Type of Professionals Living in Russia and Russian Migrants to the EU Countries

The goal of this study was to uncover the influence of professional activity, migration, and gender on dynamics of subjective age and ageing biomarkers. We examined the representatives of investigative types of professions (ITP), 30–75 years old in Russia, (101/62 women), and Russian migrants to the European Union, (101/56 women). ITPs appeared to be ageing slower than statistical standards; men age faster than women; the pre-retirement group (51–65 years old) showed acceleration of relative biological ageing in the Russian sample (women +4.5 years, men +10.7 years) against the EU sample, suggesting a boost of pre-retirement stress in Russia; subjectively, Russian people (51–65 years old) feel close to their chronological age, while EU people perceive themselves far below their calendar age (men—lower by 20.4, women—lower by 10.9 years). The subjective ageing depends on the country of residence, while biological ageing depends on occupation, gender, and negative expectations of retirement

Comparative dynamics of individual ageing among the investigative type of professionals living in Russia and russian migrants to the EU countries

The goal of this study was to uncover the influence of professional activity, migration, and gender on dynamics of subjective age and ageing biomarkers. We examined the representatives of investigative types of professions (ITP), 30–75 years old in Russia, (101/62 women), and Russian migrants to the European Union, (101/56 women). ITPs appeared to be ageing slower than statistical standards; men age faster than women; the pre-retirement group (51–65 years old) showed acceleration of relative biological ageing in the Russian sample (women +4.5 years, men +10.7 years) against the EU sample, suggesting a boost of pre-retirement stress in Russia; subjectively, Russian people (51–65 years old) feel close to their chronological age, while EU people perceive themselves far below their calendar age (men—lower by 20.4, women—lower by 10.9 years). The subjective ageing depends on the country of residence, while biological ageing depends on occupation, gender, and negative expectations of retirement

Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA

MHC class II (MHC-II) genes are regulated by an enhanceosome complex containing two gene-specific transcription factors, regulatory factor X complex (RFX) and CIITA. These factors assemble on a strictly conserved regulatory module (S-X-X2-Y) found immediately upstream of the promoters of all classical and nonclassical MHC-II genes as well as the invariant chain (Ii) gene. To identify new targets of RFX and CIITA, we developed a computational approach based on the unique and highly constrained architecture of the composite S-Y motif. We identified six novel S'-Y' modules situated far away from the promoters of known human RFX- and CIITA-controlled genes. Four are situated at strategic positions within the MHC-II locus, and two are found within the Ii gene. These S'-Y' modules function as transcriptional enhancers, are bona fide targets of RFX and CIITA in B cells and IFN-gamma-induced cells, and induce broad domains of histone hyperacetylation. These results reveal a hitherto unexpected level of complexity involving long distance control of MHC-II expression by multiple distal regulatory elements

Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA.

MHC class II (MHC-II) genes are regulated by an enhanceosome complex containing two gene-specific transcription factors, regulatory factor X complex (RFX) and CIITA. These factors assemble on a strictly conserved regulatory module (S-X-X2-Y) found immediately upstream of the promoters of all classical and nonclassical MHC-II genes as well as the invariant chain (Ii) gene. To identify new targets of RFX and CIITA, we developed a computational approach based on the unique and highly constrained architecture of the composite S-Y motif. We identified six novel S'-Y' modules situated far away from the promoters of known human RFX- and CIITA-controlled genes. Four are situated at strategic positions within the MHC-II locus, and two are found within the Ii gene. These S'-Y' modules function as transcriptional enhancers, are bona fide targets of RFX and CIITA in B cells and IFN-gamma-induced cells, and induce broad domains of histone hyperacetylation. These results reveal a hitherto unexpected level of complexity involving long distance control of MHC-II expression by multiple distal regulatory elements