Beyond A and B Compartments: how major nuclear locales define nuclear genome organization and function.

Models of nuclear genome organization often propose a binary division into active versus inactive compartments, yet they overlook nuclear bodies. Here we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Whereas gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales.

Replication timing and transcriptional control: beyond cause and effect - part IV.

Decades of work on the spatiotemporal organization of mammalian DNA replication timing (RT) continues to unveil novel correlations with aspects of transcription and chromatin organization but, until recently, mechanisms regulating RT and the biological significance of the RT program had been indistinct. We now know that the RT program is both influenced by and necessary to maintain chromatin structure, forming an epigenetic positive feedback loop. Moreover, the discovery of specific cis-acting elements regulating mammalian RT at both the domain and the whole-chromosome level has revealed multiple cell-type-specific and developmentally regulated mechanisms of RT control.

Epigenetic control of chromosome-associated lncRNA genes essential for replication and stability.

ASARs are long noncoding RNA genes that control replication timing of entire human chromosomes in cis. The three known ASAR genes are located on human chromosomes 6 and 15, and are essential for chromosome integrity. To identify ASARs on all human chromosomes we utilize a set of distinctive ASAR characteristics that allow for the identification of hundreds of autosomal loci with epigenetically controlled, allele-restricted behavior in expression and replication timing of coding and noncoding genes, and is distinct from genomic imprinting.

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki-67.

Ki-67 is a chromatin-associated protein with a dynamic distribution pattern throughout the cell cycle and is thought to be involved in chromatin organization. The lack of genomic interaction maps has hampered a detailed understanding of its roles, particularly during interphase. By pA-DamID mapping in human cell lines, we find that Ki-67 associates with large genomic domains that overlap mostly with late-replicating regions.

Mammalian DNA Replication Timing.

Immediately following the discovery of the structure of DNA and the semi-conservative replication of the parental DNA sequence into two new DNA strands, it became apparent that DNA replication is organized in a temporal and spatial fashion during the S phase of the cell cycle, correlated with the large-scale organization of chromatin in the nucleus. After many decades of limited progress, technological advances in genomics, genome engineering, and imaging have finally positioned the field to tackle mechanisms underpinning the temporal and spatial regulation of DNA replication and the causal relationships between DNA replication and other features of large-scale chromosome structure and function. In this review, we discuss these major recent discoveries as well as expectations for the coming decade.