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After deciphering the structure of DNA, it took several years to begin integrating two tightly related fields: chromosomal and nuclear cytology and the regulatory processes occurring inside the cell nucleus . An understanding of the importance of chromatin in genome organization allowed for this amalgamation. Moreover, it allowed for a more integrative view of epigenetics beyond its function in the regulation of transcriptional regulation, to nuclear dynamics, replication, DNA repair, stem cell biology, cell fate acquisition, differentiation and even cellular reprogramming .
Many questions remain open on how epigenetic processes integrate this variety of cellular functions. For example, how are external cell signals transduced and integrated at the chromatin level? How are transcription factors and remodeling complexes selectively attracted to specific sites in the genome? How does the genomic landscape depend on nuclear dynamics? What is the role of nuclear and chromatin dynamics in cell differentiation, development and disease? These topics will undoubtedly be investigated with more intensity in future years.
In this special issue of Briefings in Functional Genomics we review some aspects of our current knowledge on chromatin regulation that are helping us have an integrative view on the epigenetic regulation of nuclear dynamics and cell function.
First, Dean and collaborators describe how transcription regulatory elements control differentiation and development by affecting the expression of distal target genes. Mechanistic aspects for the establishment of chromatin loops allowing for close contacts between distal regulatory elements are discussed. The architecture of long-range interactions is a novel way to visualize transcriptional regulation that might be intimately linked to the transcription factors’ way of action, their post-translational modifications and their associated chromatin remodeling activities .
Osborne and collaborators incorporate nuclear structure and dynamics to the discussion. Their manuscript emphasizes the technical approaches to describe the relationship between nuclear sub-compartments and particular distal genomic regions that establish contacts in a regulated manner. One view is that regulated structuring of the genome determines gene distribution and favors for the establishment of functional nuclear sub-compartments regulating gene expression. This is a clear example highlighting the integration of nuclear-scale genome dynamics into the epigenetic mechanisms regulating essential aspects of cell function.
One clear demonstration of the relevance of genome dynamics at the chromosome level are the interchromosomal anomalous translocations, leading to generation of fusion proteins miss-regulating transcription of genes determining the hematopoietic lineage, and causing different types of leukemias . Di Croce and Uribesalgo describe clear examples of the interdependence between genetic and epigenetic mechanisms involved in development of acute myeloblastic leukemia. For example, the authors describe the models suggesting how the Polycomb group of proteins acts in these malignancies. The discussion in this review highlights the possibility that an integrative understanding of different epigenetic mechanisms can lead to the design of novel diagnostic and therapeutic strategies for some leukemias.
In another review, Meisch and Prioleau address an aspect of the function of chromatin that is not frequently discussed and which is critical for genome stability and cell survival. That is the contribution of chromatin structure to DNA replication. The regulated assembly of a large number of replication origins is poorly understood. In this regard, genome-wide studies provide novel insight into the mechanisms associated with site-specific DNA replication. Those studies outlined the relevant function of chromatin structure in the formation of the pre-replication complexes needed for activation of replication origins. In addition, two important issues are addressed: how the positioning of replication origin is regulated genome-wide; and what the mechanisms for temporal initiation of DNA replication are?
Finally, Delgado-Olguín and Recillas-Targa discuss the important functions of some of the general chromatin structure components in embryonic stem cell biology and in induced pluripotent stem cells. In addition to establishing gene expression networks; epigenetic silencing via DNA methylation (including no-CpG methylation), Polycomb complexes and non-coding RNAs seem to be critical for cell lineage commitment . Deeper understanding of the epigenetic processes regulating pluripotency will help us control reprogramming of somatic cells into pluripotent cells suitable for regenerative medicine.
This special issue reflects the clear expansion of the research on the many processes affected by chromatin structure. The varied and abundant findings on the implications of chromatin structure dynamics, urges for the integration of the results and models generated in order to reach a comprehensive understanding on epigenetic regulation. Now that epigenomic approaches have been generating large amounts of data, providing a global view of diverse epigenetic processes, integration of the produced knowledge should significantly further our understanding, or even change our perception of aspects of transcription, DNA repair and replication, and nuclear dynamics, among others. The field on epigenetic regulation is thus entering exciting times, and an optimistic prediction is that knowledge on the field will not only bring better diagnoses and treatment for various pathologies, but also transform the scientific approaches in many research fields ranging from molecular to behavioral biology.