It has been exactly 50 years since it was discovered that duplication of the eukaryotic genome follows a defined temporal order as cells progress through S‑phase. While the mechanism of this replication‑timing program still remains a mystery, various correlations of this program with both static and dynamic properties of chromatin render it an attractive forum to explore previously impenetrable higher‑order organization of chromosomes. Indeed, studies of DNA replication have provided a simple and straightforward approach to address physical organization of the genome, both along the length of the chromosome as well as in the context of the 3‑dimensional space in the cell nucleus. In this chapter, we summarize the 50‑years history of the pursuit for understanding the replication‑timing program and its developmental regulation, primarily in mammalian cells. We begin with the discovery of the replication‑timing program, discuss developmental regulation of this program during X‑inactivation in females as well as on autosomes and then describe the recent findings from genome‑wide dissection of this program, with special reference to what takes place during mouse embryonic stem cell differentiation. We make an attempt to interpret what these findings might represent and discuss their potential relevance to embryonic development. In doing so, we revive an old concept of “autosomal Lyonization” to describe “facultative heterochromatinization” and irreversible silencing of individual replication domains on autosomes reminiscent of the stable silencing of the inactive X chromosome, which takes place at a stage equivalent to the postimplantation epiblast in mice.
Transcriptional regulation is a pivotal process that confers cellular identity and modulates the biological activities within a cell. In embryonic stem cells (ESCs), the intricate interplay between transcription factors and their targets on the genomic template serves as building blocks for...
X chromosome inactivation (XCI) is a process required to equalize the dosage of X‑encoded genes between female and male cells. XCI is initiated very early during female embryonic development or upon differentiation of female embryonic stem (ES) cells and results in inactivation of one X...
During development, initially totipotent cells of the embryo specialize to form discrete tissue lineages. The first lineages to form in the mouse are the extraembryonic tissues. Meanwhile, cells that do not become extraembryonic retain a pluripotent fate since they can give rise to all the...
Stem cell differentiation requires a complex coordination of events to transition from a self‑renewing to a differentiated cell fate. Stem cells can be pluripotent (capable of giving rise to all embryonic lineages), multipotent (possessing the potential to give rise to multiple lineages) and...
Epigenetic regulation refers to the mechanisms that alter gene expression patterns in the absence of changes in the nucleotide sequence of the DNA molecule. The best understood epigenetic marks include posttranslational modifications of the histone tails and DNA methylation. Both play central...
It has been exactly 50 years since it was discovered that duplication of the eukaryotic genome follows a defined temporal order as cells progress through S‑phase. While the mechanism of this replication‑timing program still remains a mystery, various correlations of this program with both...
There are several animal model organisms that have the ability to regenerate severe injuries by stimulating local cells to restore damaged and lost organs and appendages. In this chapter, we will describe how various vertebrate animals regenerate different structures (central nervous system,...
Telomerase expression is silenced in most adult somatic tissues with the exception of adult stem cell (SC) compartments, which have the property of having the longest telomeres within a given tissue. Adult SC compartments suffer from telomere shortening associated with organismal aging until...
This chapter provides a review of recent advances in understanding the importance of alternative pre‑messenger RNA splicing in stem cell biology. The majority of transcribed pre‑mRNAs undergo RNA splicing where introns are excised and exons are juxtaposed to form mature messenger RNA...
Fundamental features of genome regulation depend on the linear DNA sequence, cell type specific modification of DNA and chromatin‑associated proteins, which locally control the expression of single genes. Architectural features of genome organization within the three‑dimensional (3D)...
Stem cells participate in dynamic physiologic systems that dictate the outcome of developmental events and organismal stress, Since these cells are fundamental to tissue maintenance and repair, the signals they receive play a critical role in the integrity of the organism. Much work has...
Embryonic stem (ES) cells and germ cells have the potential to give rise to an entire organism. A common requirement is that both must have very robust mechanisms to preserve the integrity of their genomes. This is particularly true since somatic cells have very high mutation frequencies...
Reprogramming of somatic cells into pluripotent stem cells has been achieved by introducing four transcription factors, Sox2, Oct3/4, Klf4 and c‑Myc, in 2006. These induced pluripotent stem (iPS) cells have raised hopes for a new era of regenerative medicine because they can avoid the...
Stem cells are unspecialized precursor cells that mainly reside in the bone marrow and have important roles in the establishment of embryonic tissue. They also have critical functions during adulthood, where they replenish short‑lived mature effector cells and regeneration of injured tissue....