This review describes new developments in the study of transgenerational epigenetic inheritance, a component of epigenetics. We start by examining the basic concepts of the field and the mechanisms that underlie epigenetic inheritance. We present a comprehensive review of transgenerational cellular epigenetic inheritance among different taxa in the form of a table, and discuss the data contained therein. The analysis of these data shows that epigenetic inheritance is ubiquitous and suggests lines of research that go beyond present approaches to the subject. We conclude by exploring some of the consequences of epigenetic inheritance for the study of evolution, while also pointing to the importance of recognizing and understanding epigenetic inheritance for practical and theoretical issues in biology.

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Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution

Molecular basis of the effects of shear stress on vascular endothelial cells.

http://www.hu.ufsc.br/projeto_hpv/The%20papillomavirus%20life%20cycle.pdf

The papillomavirus life cycle.

Recently, MYC has been shown to serve as a direct regulator of ribosome biogenesis and therefore coordinates protein synthesis. Could the regulation of ribosome biogenesis by MYC be necessary for its role in tumorigenesis? MYC regulates the transcription of thousands of genes required to coordinate a range of cellular processes, including those essential for proliferation, growth, differentiation, apoptosis and self-renewal. Recently, MYC has also been shown to serve as a direct regulator of ribosome biogenesis. MYC coordinates protein synthesis through the transcriptional control of RNA and protein components of ribosomes, and of gene products required for the processing of ribosomal RNA, the nuclear export of ribosomal subunits and the initiation of mRNA translation. We discuss how the modulation of ribosome biogenesis by MYC may be essential to its physiological functions as well as its pathological role in tumorigenesis.

MYC as a regulator of ribosome biogenesis and protein synthesis

http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Doencas/do-1527.pdf

Ribosomopathies: human disorders of ribosome dysfunction.

Ribosome biogenesis has been associated with regulation of cell growth and cell division, but the molecular mechanisms that integrate the effect of ribosome biogenesis on these processes in mammalian cells remain unknown. To study the effect of impaired ribosome functions in vivo, we conditionally deleted one or two alleles of the 40S ribosomal protein S6 gene in T cells in the mouse. While complete deletion of S6 abrogated T-cell development, hemizygous expression did not have any effect on T-cell maturation in the thymus, but inhibited the accumulation of T cells in the spleen and lymph nodes, as a result of their decreased survival in the peripheral lymphoid organs. Additionally, TCR-mediated stimulation of S6-heterozygous T cells induced a normal increase in their size, but cell cycle progression was impaired. Genetic inactivation of p53 tumor suppressor rescued development of S6-homozygous null thymocytes and proliferative defect of S6-heterozygous T cells. These results demonstrate the existence of a p53-dependent checkpoint mechanism that senses changes in the fidelity of the translational machinery to prevent aberrant cell division or eliminate defective T cells in vivo. Failure to activate this checkpoint response could potentially lead to a development of pathological processes such as tumors and autoimmune diseases.

/pdf/inactivation-of-s6-ribosomal-protein-gene-in-t-lymphocytes-4m1jl5mqxg.pdf

Inactivation of S6 ribosomal protein gene in T lymphocytes activates a p53-dependent checkpoint response

Nascent ribosome biogenesis is required during cell growth. To gain insight into the importance of this process during mouse oogenesis and embryonic development, we deleted one allele of the ribosomal protein S6 gene in growing oocytes and generated S6-heterozygous embryos. Oogenesis and embryonic development until embryonic day 5.5 (E5.5) were normal. However, inhibition of entry into M phase of the cell cycle and apoptosis became evident post-E5.5 and led to perigastrulation lethality. Genetic inactivation of p53 bypassed this checkpoint and prolonged development until E12.5, when the embryos died, showing decreased expression of D-type cyclins, diminished fetal liver erythropoiesis, and placental defects. Thus, a p53-dependent checkpoint is activated during gastrulation in response to ribosome insufficiency to prevent improper execution of the developmental program.

Ribosomal Protein S6 Gene Haploinsufficiency Is Associated with Activation of a p53-Dependent Checkpoint during Gastrulation

Hypomorphic mutation in one allele of ribosomal protein l24 gene (Rpl24) is responsible for the Belly Spot and Tail (Bst) mouse, which suffers from defects of the eye, skeleton, and coat pigmentation. It has been hypothesized that these pathological manifestations result exclusively from faulty protein synthesis. We demonstrate here that upregulation of the p53 tumor suppressor during the restricted period of embryonic development significantly contributes to the Bst phenotype. However, in the absence of p53 a large majority of Rpl24(Bst/+) embryos die. We showed that p53 promotes survival of these mice via p21-dependent mechanism. Our results imply that activation of a p53-dependent checkpoint mechanism in response to various ribosomal protein deficiencies might also play a role in the pathogenesis of congenital malformations in humans.

Martina Barkić

Papers

Inactivation of S6 ribosomal protein gene in T lymphocytes activates a p53-dependent checkpoint response

Ribosomal Protein S6 Gene Haploinsufficiency Is Associated with Activation of a p53-Dependent Checkpoint during Gastrulation

The p53 Tumor Suppressor Causes Congenital Malformations in Rpl24-Deficient Mice and Promotes Their Survival