Biology subjects

Völker-Albert, M.

Publications and source records attributed to Völker-Albert, M..

3 recordsLinked to original sources

bioRxiv2025

RIF1 orchestrates a multi-step restoration of post-replicative H3K9me3

DNA replication causes the dilution of parental histones along with their specific post-translational modifications. The kinetics of restoring these marks on newly incorporated histones dictate how quickly genomic domains regain their epigenetic identity after replication. H3K9me3 is restored extremely slowly; the process of reconstitution, to achieve the pre-replication levels, continues throughout the following G1 phase. The molecular mechanisms behind this slow reconstitution are unknown. We show here that RIF1s reassociation with heterochromatin during mitotic exit is required to set up a chromatin environment permissive for histone methyltransferases to resume H3K9me3 deposition. RIF1 facilitates the recruitment of SUV39H1, HP1 and HP1{beta} and is required for the increased tri-methylation of H3K9 that occurs during G1 phase. RIF1 is also indispensable for recruiting Protein Phosphatase 1 (PP1) to heterochromatin, and the interaction between RIF1 and PP1 is essential for the maintenance of H3K9me3 levels. In addition, RIF1-PP1 complex temporally restrains the activity of Aurora kinase at heterochromatin, ensuring that phosphorylation of H3S10 does not precede replication. This creates a time- window permissive for SUV39Hs to initiate the reinstatement of H3K9me3.

cell biology↗

bioRxiv2025

Spatially resolved mapping of histones reveal selective neuronal response in Rett syndrome

Rett Syndrome (RTT), a severe neurological disorder caused by loss-of-function mutations in the X-linked MECP2 gene, results in profound life-long neurological dysfunction. RTT patients live an apparently normal initial life until 12-18 months of age following which, a progressive accumulation of a wide range of phenotypic manifestations sets in. While MeCP2 is known to regulate chromatin, its impact on global histone composition and dynamics remains poorly understood. Here, we combine mass spectrometry imaging (MSI) and laser capture microdissection (LCM) coupled to LC-MS/MS to systematically profile histone proteoforms in three key brain regions: the dentate gyrus (DG) and cornu ammonis (CA) of the hippocampus, and the cerebellum (Cb). Our analysis reveals striking neuron-specific differences in histone composition between Mecp2-deficient and wildtype (WT) mice. Interestingly, the expression of a pathogenic Mecp2 missense mutant (Y120D) results in subtler changes in histone composition that are distinct from the null mutations. This study provides the first spatially resolved epigenetic atlas of histone proteoforms in RTT and suggests that Mecp2 loss perturbs chromatin homeostasis in a neuron- and mutation-dependent manner. Our findings underscore the critical need for cell-type-resolved analyses to unravel the mechanistic underpinnings of RTT and emphasize the importance of personalised therapeutic strategies that consider both the affected cell-type and particular Mecp2 mutation.

neuroscience↗

bioRxiv2019

Domain model explains propagation dynamics and stability of K27 and K36 methylation landscapes

Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle and the principles governing heritability remain unclear. Here, we take a quantitative computational modeling approach to describes propagation of K27 and K36 methylation states. We measure combinatorial K27 and K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that K27me3 on pre-existing histones stimulates the rate of de novo K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed, quantitative picture of the mutual antagonism between K27 and K37 methylation, and propose that it stabilizes epigenetic states across cell division.

systems biology↗