Centromere

Summary

The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers attach to the centromere via the kinetochore. The physical role of the centromere is to act as the site of assembly of the kinetochores – a highly complex multiprotein structure that is responsible for the actual events of chromosome segregation – i.e. binding microtubules and signaling to the cell cycle machinery when all chromosomes have adopted correct attachments to the spindle, so that it is safe for cell division to proceed to completion and for cells to enter anaphase. There are, broadly speaking, two types of centromeres. "Point centromeres" bind to specific proteins that recognize particular DNA sequences with high efficiency. Any piece of DNA with the point centromere DNA sequence on it will typically form a centromere if present in

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Centromeres are dismantled by foundational meiotic proteins Spo11 and Rec8

Eftychia Kyriacou

Meiotic processes are potentially dangerous to genome stability and could be disastrous if activated in proliferative cells. Here we show that two key meiosis-defining proteins, the topoisomerase Spo11 (which forms double-strand breaks) and the meiotic cohesin Rec8, can dismantle centromeres. This dismantlement is normally observable only in mutant cells that lack the telomere bouquet, which provides a nuclear microdomain conducive to centromere reassembly(1); however, overexpression of Spo11 or Rec8 leads to levels of centromere dismantlement that cannot be countered by the bouquet. Specific nucleosome remodelling factors mediate centromere dismantlement by Spo11 and Rec8. Ectopic expression of either protein in proliferating cells leads to the loss of mitotic kinetochores in both fission yeast and human cells. Hence, while centromeric chromatin has been characterized as extraordinarily stable, Spo11 and Rec8 challenge this stability and may jeopardize kinetochores in cancers that express meiotic proteins.

NATURE RESEARCH2021

Accurate spatio-temporal control of Hox cluster genes expression is critical for the proper organization of body structures during vertebrate embryogenesis. In the limbs, Hoxd genes are critical in setting up the proximodistal and anteroposterior axes. Several studies have shown that long-range global regulatory elements are required to establish Hoxd genes expression territories in this tissue, via the co-regulation of several genes at once. Limb buds take their origin from the lateral plate mesoderm where the HoxD cluster is controlled by cues from the main body axis. During limb outgrowth Hoxd genes are then subjected to two subsequent activation waves: an early phase patterning proximal limb structures, arms and forearms and a late one instructing digits. As the late activation of Hoxd genes is known to rely upon a large regulatory archipelago located centromeric to the gene cluster, the control of the early phase remains poorly described (Montavon et al., 2011). In this work we show that the early activation domain requires a different, telomeric-located, regulatory landscape. This one megabase (Mb) large domain holds at least three regulatory regions contributing to Hoxd gene activation in early forelimb and hindlimb buds. To our surprise the abrogation of most of the early telomeric enhancers induced a dramatic decrease of central Hoxd transcription in forelimbs but only removed 50% of the transcripts in hindlimbs. This discrepancy most likely arises from the difference in the epigenetic status of the HoxD cluster in anterior and posterior limb fields where forelimb and hindlimb respectively take their origin. As the cluster does not possess the same fraction of active genes in these progenitors it most likely does not respond to early cues in the same way. In the second part of this work we noticed an unexpected decrease of the late expression phase in all mutants lacking early enhancers. This observation shows that digit progenitors have to implement the early phase in order to gain competence toward the late centromeric regulation. This transition between early and late regulations involves a set of central Hoxd genes, i.e. Hoxd11 to Hoxd9. To implement both regulations, these loci switch between two topological domains containing the centromeric and telomeric regulatory landscapes respectively (Dixon et al., 2012). The ability to switch from one domain to another depends on the relative position of genes towards the boundary between both domains and correlates with their respective expression. Moreover, the switch between both topological domains mechanically induces an intermediate, Hoxd-free zone, in-between the two expression phases that will later produce the mesopodium, the articulation between our arms and our hands.

EPFL2013

Telomeres are nucleoprotein structures present in the end of linear chromosomes. In humans, a core complex of 6 proteins cap and protect the chromosome ends from being recognized as double-strand breaks and eliciting unwanted DNA damage and repair responses, which lead to chromosomal end-to-end fusions and genomic instability. In addition to the shelterins, another 200 proteins are detected at telomeres by mass spectrometry. Their functions at telomere are not yet completely understood. Telomeres are transcribed into a long non-coding RNA called TERRA. It is believed that subtelomeric CpG islands act as TERRA promoters. TERRA is suggested to regulate telomerase activity, to participate in the processing of uncapped telomeres, in telomeric heterochromatin formation and in promoting recombination-mediated telomere elongation. TERRA levels are increased in patients affected by the ICF (immunodeficiency, centromeric instability, facial anomalies) syndrome. Since these patients also present very short telomeres, it has been suggested that TERRA regulates telomere length, either by inhibiting telomerase or by promoting access to end-attacking nucleases. We used HCT116 DNMT1 (deletion of exons3-5/exons3-5) DNMT3B (-/-) (DKO) cells as a model for the ICF syndrome to try to comprehend the relationship between TERRA expression and telomere length. In this thesis, we try to understand (1) if there is a direct correlation between TERRA expression and telomere length, (2) what drives TERRA transcription, (3) what are the consequences of TERRA overexpression, and (4) what could cause the short telomere phenotype in DKO cells. We show that not all telomeres overexpress TERRA in DKO cells, but even telomeres with normal TERRA expression are short. By analyzing subtelomeric sequences, we found that the presence and density of subtelomeric CpG islands determine if its transcript will be upregulated in DKO cells or not. We used absolute quantification methods to demonstrate that TERRA is expressed from multiple chromosome ends, disproving a recent proposal that TERRA stems only from one locus. We also discovered that CpG-negative subtelomeres express TERRA in levels similar to CpG-positive ones, suggesting that the presence of subtelomeric CpG-islands is not a requirement for high TERRA expression. We next evaluated the telomere length dynamics in DKO cells. We found that DKO cells show lower telomere elongation rates than the WT. Moreover, DKO cells fail to downregulate TERRA in S-phase, in contrast to WT HCT116 and HeLa cells. The downregulation of TERRA in late S-phase has been proposed to alleviate TERRA-dependent telomerase inhibition and thereby allow the enzyme to extend short telomeres. To better understand TERRA transcription, we performed a siRNA screen to discover new TERRA transcription regulators. We found ZNF148, ZFX, PLAG1 and EGR1 to be new repressors of TERRA transcription. Finally, we established a CRISPR activation system to induce overexpression of endogenous TERRA. Overexpression of 10q and 13q TERRA in HCT116 did not lead to telomere shortening in cis. In HeLa cells, overexpression of multiple TERRA species led to deposition of the heterochromatin marks H3K9me3 and H4K20me3 in the telomeres. These marks were also enriched in subtelomeric sequences in cis. Since TERRA has been shown to interact with SUV39H1 to ensure H3K9me3 deposition, we speculate that TERRA also recruits SUV420H2 to induce H4K20me3 accumulation.

EPFL2019