Centromere and Pericentromere Transcription: Roles and Regulation … in Sickness and in Health

Abstract

The chromosomal loci known as centromeres (CEN) mediate the equal distribution of the duplicated genome between both daughter cells. Specifically, centromeres recruit a protein complex named the kinetochore, that bi-orients the replicated chromosome pairs to the mitotic or meiotic spindle structure. The paired chromosomes are then separated, and the individual chromosomes segregate in opposite direction along the regressing spindle into each daughter cell. Erroneous kinetochore assembly or activity produces aneuploid cells that contain an abnormal number of chromosomes. Aneuploidy may incite cell death, developmental defects (including genetic syndromes), and cancer (>90% of all cancer cells are aneuploid). While kinetochores and their activities have been preserved through evolution, the CEN DNA sequences have not. Hence, to be recognized as sites for kinetochore assembly, CEN display conserved structural themes. In addition, CEN nucleosomes enclose a CEN-exclusive variant of histone H3, named CENP-A, and carry distinct epigenetic labels on CENP-A and the other CEN histone proteins. Through the cell cycle, CEN are transcribed into non-coding RNAs. After subsequent processing, they become key components of the CEN chromatin by marking the CEN locus and by stably anchoring the CEN-binding kinetochore proteins. CEN transcription is tightly regulated, of low intensity, and essential for differentiation and development. Under- or overexpression of CEN transcripts, as documented for myriad cancers, provoke chromosome missegregation and aneuploidy. CEN are genetically stable and fully competent only when they are insulated from the surrounding, pericentromeric chromatin, which must be silenced. We will review CEN transcription and its contribution to faithful kinetochore function. We will further discuss how pericentromeric chromatin is silenced by RNA processing and transcriptionally repressive chromatin marks. We will report on the transcriptional misregulation of (peri)centromeres during stress, natural aging, and disease and reflect on whether their transcripts can serve as future diagnostic tools and anti-cancer targets in the clinic.

Human chromosome‐specific aneuploidy is influenced by DNA ‐dependent centromeric features

“…In any case, CENP-A has a similar centromere enrichment profile to that of CENP-B (Fig EV5F and G), in accordance to the fact that CENP-A binding is proportional to centromere length [it tends to occupy~25-30% of the higher order repeats array (Sullivan et al, 2011); Table EV2]. Other (peri-)centromeric features could impact on chromosome-specific aneuploidy in a kinetochore-independent manner, among which we can mention variations within HOR arrays such as SNPs and indels (Sullivan et al, 2017), changes in the heterochromatin surrounding functional centromeres (Pezer & Ugarkovi c, 2008), fluctuations in centromere transcripts (Smurova & De Wulf, 2018), DNA methylation (Scelfo & Fachinetti, 2019), and variation in centromeric cohesion (Kitajima et al, 2006) and/or in microtubule-destabilizing activity (Akera et al, 2019). All these factors can potentially promote different patterns of chromosomespecific aneuploidy.…”

Exosomes transmit retroelement RNAs to drive inflammation and immunosuppression in Ewing Sarcoma

“…Among 297 upregulated mRNAs, there were IRF7, IL8, IL32, TNFRSF14 and MB21D1/CGAS ( Fig.5e and Extended Data Table 6b), consistent with the observed activation of antiviral and proinflammatory responses. However, the largest group of upregulated mRNAs (54 of 297) were those encoding centromeric proteins and kinetochore complex assembly components ("CENPA/NDC80" module), key regulators of centrosome maturation, spindle assembly and chromatin condensation ("PLK1/NEK2" module), and other cell division and DNA damage control proteins ("BRCA1/TOP2A" module; Fig.5f and Extended Data Table 6c), all of which are known to be involved in pericentromeric heterochromatin maintenance 29,44,45 . Activation of these pathways may thus be indicative of extensive centromeric heterochromatin remodelling in recipient cells.…”

Heat Shock Affects Mitotic Segregation of Human Chromosomes Bound to Stress-Induced Satellite III RNAs

“…However, the validity of this mechanism in mammalian cells is still weak since short pericentromeric RNAs in vertebrate cells are difficult to detect. On the other hand, the role of pericentromeric transcripts in the assembly, maintenance and function of heterochromatin in mammals is substantial [12]. It is noteworthy that in primary mouse embryonic fibroblasts, transcription of pericentromeric heterochromatin is controlled during the cell cycle [13] with the production of long, heterogeneous transcripts in G1 and a pool of shorter transcripts (∼200 nt) at mitotic onset.…”