Band 6, Heft 2

Transgenerational epigenetic inheritance in animals has increasingly been reported in recent years. Controversies, however, surround this unconventional mode of heredity, especially in mammals, for several reasons. First, its existence itself has been questioned due to perceived insufficiency of available evidence. Second, it potentially implies transfer of hereditary information from soma to germline, against the established principle in biology. Third, it inherently requires survival of epigenetic memory across reprogramming, posing another fundamental challenge in biology. Fourth, evolutionary significance of epigenetic inheritance has also been under debate. This article pointwise addresses all these concerns on the basis of recent empirical, theoretical and conceptual advances. 1) Described here in detail are the key experimental findings demonstrating the occurrence of germline epigenetic inheritance in mammals. 2) Newly emerging evidence supporting soma to germline communication in transgenerational inheritance in mammals, and a role of exosome and extracellular microRNA in this transmission, is thoroughly discussed. 3) The plausibility of epigenetic information propagation across reprogramming is highlighted. 4) Analyses supporting evolutionary significance of epigenetic inheritance are briefly mentioned. Finally, an integrative model of ‘evolutionary transgenerational systems biology’ is proposed to provide a framework to guide future advancements in epigenetic inheritance.

Many aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity.

The ability to regulate gene expression in response to environmental alterations is vital for the endurance of all cells. However, unlike bacteria and unicellular organisms, cells of multicellular eukaryotes have developed this competency in a highly sophisticated manner, which ultimately allows for multiple lineages of differentiated cells. To maintain stability and generate progeny, differentiated cells must remain lineage-committed through numerous cell generations, and therefore their transcriptional modus operandi ought to be memorized and transmittable. To preserve the specialized characteristics of differentiated cells, it is crucial that transcriptional alterations that are triggered by specific external or intrinsic stimuli can last also after stimuli fading and propagate onto daughter cells. The unique composition of DNA and histones, and their ability to acquire a variety of epigenetic modifications, enables eukaryotic chromatin to assimilate cellular plasticity and molecular memory. The most well-studied types of epigenetic modifiers are covalently modifying DNA or histones, mostly in a reversible manner. Additional epigenetic mechanisms include histone variant replacement, energy-utilizing remodeling factors, and noncoding transcripts assembled with modifying complexes. Working with multifunctional complexes including transcription factors, epigenetic modifiers have the potential to dictate a variety of transcriptional programs underlying all cellular lineages, while utilizing in each the same source DNA as their substrates.

Vertebrate heart formation is a spatiotemporally regulated morphogenic process that initiates with bilaterally symmetric cardiac primordial cells migrating toward the midline to form a linear heart tube. The heart tube then elongates and undergoes a series of looping morphogenesis, followed by expansions of regions that are destined to become primitive heart chambers. During the cardiac morphogenesis, cells derived from the first heart field contribute to the primary heart tube, and cells from the secondary heart field, cardiac neural crest, and pro-epicardial organ are added to the heart tube in a precise spatiotemporal manner. The coordinated addition of these cells and the accompanying endocardial cushion morphogenesis yield the atrial, ventricular, and valvular septa, resulting in the formation of a four-chambered heart. Perturbation of progenitor cells’ deployment and differentiation leads to a spectrum of congenital heart diseases. Two of the genes that were recently discovered to be involved in cardiac morphogenesis are Numb and Numblike . Numb, an intracellular adaptor protein, distinguishes sibling cell fates by its asymmetric distribution between the two daughter cells and its ability to inhibit Notch signaling. Numb regulates cardiac progenitor cell differentiation in Drosophila and controls heart tube laterality in Zebrafish . In mice, Numb and Numblike, the Numb family proteins (NFPs), function redundantly and have been shown to be essential for epicardial development, cardiac progenitor cell differentiation, outflow tract alignment, atrioventricular septum morphogenesis, myocardial trabeculation, and compaction. In this review, we will summarize the functions of NFPs in cardiac development and discuss potential mechanisms of NFPs in the regulation of cardiac development.

MicroRNAs are short non-coding RNA molecules encoded by distinct genes involved in the posttranscriptional regulation of gene expression. Forming part of the epigenetic machinery, microRNAs are involved in several aspects of tumorigenesis. Deregulation of microRNA expression is a common feature of tumors. Overexpressed oncogenic and underexpressed tumor suppressor microRNAs have been described in many different tumors. MicroRNAs are released from tumors that might affect other cells within and outside the tumor. Circulating microRNAs might also be involved in a tumor surveillance mechanism. In this short overview, some important aspects of microRNA in tumors are discussed.

Emerging evidence suggests that components of the small RNAs pathway interact with chromatin to regulate nuclear events, such as gene transcription. However, it has recently been reported that in some cases, gene transcription regulation by cellular miRNAs can occur via targeting the TATA-box motif without altering epigenetic modifications. This observation supports the notion that multiple mechanisms of miRNA-based transcriptional regulation exist, enhancing our understanding of the complexity of small RNA-mediated gene regulatory pathways. Here, we remark that miRNA-mediated transcriptional modulation, through the TATA-box motif, may be a synergistic approach for transcriptional control.