A genetic memory initiates the epigenetic loop necessary to preserve centromere position

Abstract

Centromeres are built on repetitive DNA sequences (CenDNA) and a specific chromatin enriched with the histone H3 variant CENP-A, the epigenetic mark that identifies centromere position. Here, we interrogate the importance of CenDNA in centromere specification by developing a system to rapidly remove and reactivate CENP-A (CENP-A OFF/ ON). Using this system, we define the temporal cascade of events necessary to maintain centromere position. We unveil that CENP-B bound to CenDNA provides memory for maintenance on human centromeres by promoting de novo CENP-A deposition. Indeed, lack of CENP-B favors neocentromere formation under selective pressure. Occasionally, CENP-B triggers centromere re-activation initiated by CENP-C, but not CENP-A, recruitment at both ectopic and native centromeres. This is then sufficient to initiate the CENP-A-based epigenetic loop. Finally, we identify a population of CENP-A-negative, CENP-B/C-positive resting CD4 + T cells capable to re-express and reassembles CENP-A upon cell cycle entry, demonstrating the physiological importance of the genetic memory.

Induction of spontaneous human neocentromere formation and long-term maturation

“…A subset of these repeats (except on the Y chromosome) contains a motif for the binding of CENP-B, a centromeric protein that interacts with DNA in a sequence-specific manner ( Earnshaw et al, 1987 ; Masumoto et al, 1989 ; Muro et al, 1992 ). However, despite contributing to centromere fidelity ( Fachinetti et al, 2015 ; Hoffmann et al, 2016 ; Dumont et al, 2020 ; Hoffmann et al, 2020 ), centromeric DNA is not strictly required for centromere function, nor is it by itself sufficient to initiate centromere function ( Earnshaw and Migeon, 1985 ). Instead, centromeres are primarily defined by specialized chromatin featuring the histone H3 variant CENP-A ( Black and Cleveland, 2011 ).…”

CENP-B promotes the centromeric localization of ZFAT to control transcription of noncoding RNA

“…CENP-B binds to a 17-bp consensus motif at the centromere, named the CENP-B box, at the N-terminal region ( 22 , 23 ). The role of CENP-B at the centromere had remained elusive for years until several recent studies have demonstrated that CENP-B plays an essential role in centromere functions ( 24 , 25 , 26 , 27 ). The binding of CENP-B at the centromere is required for the establishment and maintenance of the centromere through its interaction with CENP-A and CENP-C.…”

Centromeres: genetic input to calibrate an epigenetic feedback loop

“…In this issue of The EMBO Journal , Fachinetti and coworkers (Hoffmann et al , ) help to elucidate the role of centromeric DNA at existing functional centromeres. Their approach is to abruptly deplete CENP‐A, thereby turning off the CENP‐A epigenetic feedback loop.…”

“…Finally, the results by Hoffmann et al () indicate that if sufficient CENP‐A is resynthesized following depletion, then CENP‐A can be reloaded to pre‐depletion levels within a single cell cycle. This observation challenges the classic self‐templating model of centromere inheritance, in which “old” chromatin‐bound CENP‐A is critical to recruit new CENP‐A as recently formalized by Pan et al (), at least in the strict stoichiometric sense.…”