Modes of Retrotransposition of Long Interspersed Element-1 by Environmental Factors

Approximately 42% of the human genome is composed of endogenous retroelements, and the major retroelement component, long interspersed element-1 (L1), comprises ∼17% of the total genome. A single human cell has more than 5 × 105 copies of L1, 80∼100 copies of which are competent for retrotransposition (RTP). Notably, L1 can induce RTP of other retroelements, such as Alu and SVA, and is believed to function as a driving force of evolution. Although L1-RTP during early embryogenesis has been highlighted in the literature, recent observations revealed that L1-RTP also occurs in somatic cells. However, little is known about how environmental factors induce L1-RTP. Here, we summarize our current understanding of the mechanism of L1-RTP in somatic cells. We have focused on the mode of L1-RTP that is dependent on the basic helix–loop–helix/per–arnt–sim (bHLH/PAS) family of transcription factors. Along with the proposed function of bHLH/PAS proteins in environmental adaptation, we discuss the functional linking of L1-RTP and bHLH/PAS proteins for environmental adaptation and evolution

Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles

初期化を阻害する転写因子が分化を促進する. 京都大学プレスリリース. 2013-04-02.Transcription factors (TFs) are able to regulate differentiation-related processes, including dedifferentiation and direct conversion, through the regulation of cell type-specific transcriptional profiles. However, the functional interactions between the TFs regulating different transcriptional profiles are not well understood. Here, we show that the TFs capable of inducing cell type-specific transcriptional profiles prevent the dedifferentiation induced by TFs for pluripotency. Of the large number of TFs expressed in a neural-lineage cell line, we identified a subset of TFs that, when overexpressed, strongly interfered with the dedifferentiation triggered by the procedure to generate induced pluripotent stem cells. This interference occurred through a maintenance mechanism of the cell type-specific transcriptional profile. Strikingly, the maintenance activity of the interfering TF set was strong enough to induce the cell line-specific transcriptional profile when overexpressed in a heterologous cell type. In addition, the TFs that interfered with dedifferentiation in hepatic-lineage cells involved TFs with known induction activity for hepatic-lineage cells. Our results suggest that dedifferentiation suppresses a cell type-specific transcriptional profile, which is primarily maintained by a small subset of TFs capable of inducing direct conversion. We anticipate that this functional correlation might be applicable in various cell types and might facilitate the identification of TFs with induction activity in efforts to understand differentiation

Specificity and disease in the ubiquitin system

Post-translational modification (PTM) of proteins by ubiquitination is an essential cellular regulatory process. Such regulation drives the cell cycle and cell division, signalling and secretory pathways, DNA replication and repair processes and protein quality control and degradation pathways. A huge range of ubiquitin signals can be generated depending on the specificity and catalytic activity of the enzymes required for attachment of ubiquitin to a given target. As a consequence of its importance to eukaryotic life, dysfunction in the ubiquitin system leads to many disease states, including cancers and neurodegeneration. This review takes a retrospective look at our progress in understanding the molecular mechanisms that govern the specificity of ubiquitin conjugation

Structural insights into the catalysis and regulation of E3 ubiquitin ligases

Covalent attachment (conjugation) of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes, including apoptosis, cell division and immune responses. Ubiquitylation was originally associated with protein degradation, but it is now clear that ubiquitylation also mediates processes such as protein–protein interactions and cell signalling depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyse the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin-conjugating enzymes (E2s) to substrates. In humans, more than 600 E3s contribute to determining the fates of thousands of substrates; hence, E3s need to be tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s function on a structural level and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin. Insights regarding the mechanisms of E3 regulation, including structural aspects of their autoinhibition and activation are also emerging