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9p21 locus is one of the most reproducible regions in genome-wide association studies (GWAS). The region harbors CDKN2A/B genes that code for p16INK4a, p15INK4b, and p14ARF proteins, and it also harbors a long gene desert adjacent to these genes. The polymorphisms that are associated with several diseases and cancers are present in these genes and the gene desert region. These proteins are critical cell cycle regulators whose transcriptional dysregulation is strongly linked with cellular regeneration, stemness, aging, and cancers. Given the importance of this locus, intense scientific efforts on understanding the regulation of these genes via promoter-driven mechanisms and recently, via the distal regulatory mechanism have provided major insights. In this review, we describe these mechanisms and propose the ways by which this locus can be targeted in pathologies and aging.

Facultative heterochromatin forms and reorganizes in response to external stimuli. However, how the initial establishment of such a chromatin state is regulated in cell-cycle-arrested cells remains unexplored. Mouse gonocytes are arrested male germ cells, at which stage the genome-wide DNA methylome forms. Here, we discovered transiently accessible heterochromatin domains of several megabases in size in gonocytes and named them differentially accessible domains (DADs). Open DADs formed in gene desert and gene cluster regions, primarily at transposons, with the reprogramming of histone marks, suggesting DADs as facultative heterochromatin. De novo DNA methylation took place with two waves in gonocytes: the first region specific and the second genome-wide. DADs were resistant to the first wave and their opening preceded the second wave. In addition, the higher-order chromosome architecture was reorganized with less defined chromosome compartments in gonocytes. These findings suggest that multiple layers of chromatin reprogramming facilitate de novo DNA methylation. • Chromosomes in gonocytes contain differentially accessible domains (DADs) • Young LINE-1 elements in DADs become activated in the middle of the gonocyte stage • DADs are resistant to the first wave of de novo DNA methylation • 3D chromosome organization is reprogrammed in gonocytes Genome-wide de novo DNA methylation occurs in mouse gonocytes, arrested male embryonic germ cells. However, how the methylome gets established in the genome of arrested cells remains unexplored. Yamanaka et al. report that multiple chromatin reprogramming pathways allow the access of methyltransferases to DNA in gonocytes. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) has an apparent hereditary component, as evidenced by the well-characterized genetic syndromes and family history associated with the increased risk of this disease. However, in a large fraction of CRC cases, no known genetic syndrome or family history can be identified, suggesting the presence of "missing heritability" in CRC etiology. The genome-wide association study (GWAS) platform has led to the identification of multiple replicable common genetic variants associated with CRC risk. These newly discovered genetic variations might account for a portion of the missing heritability. Here, we summarize the recent GWASs related to newly identified genetic variants associated with CRC risk and clinical outcome. The findings from these studies suggest that there is a lack of understanding of the mechanism of many single nucleotide polymorphisms (SNPs) that are associated with CRC. In addition, the utility of SNPs as prognostic markers of CRC in clinical settings remains to be further assessed. Finally, the currently validated SNPs explain only a small fraction of total heritability in complex-trait diseases like CRC. Thus, the "missing heritability" still needs to be explored further. Future epidemiological and functional investigations of these variants will add to our understanding of CRC pathogenesis, and may ultimately lead to individualized strategies for prevention and treatment of CRC.