New and Old Histones in Epigenetic Cell Memory

Informations projet

HISTONEMEMORY

N° de convention de subvention: 724436

DOI

10.3030/724436

Projet clôturé

Date de signature de la CE 13 Mars 2017

Date de début 1 Mai 2017

Date de fin 30 Avril 2022

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 999 750,00

Contribution de l’UE

€ 1 999 750,00

Coordonné par

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 4 - HISTONEMEMORY (New and Old Histones in Epigenetic Cell Memory)

Période du rapport: 2021-11-01 au 2022-04-30

Résumé du contexte et des objectifs généraux du projet

Cell type specific organization of DNA into chromatin is an important determinant of gene expression and cell identity. During cell division, epigenetic information in chromatin must be transmitted to daughter cells in order to maintain cell identity or commit to a developmental program. However, it remains unknown how epigenetic states are inherited during cell division. Elucidating molecular mechanisms underlying epigenetic cell memory thus represents a major challenge in biology critical to understand development and disease.
Chromatin undergoes genome-wide disruption during DNA replication and histone marks are diluted 2-fold due to new histone deposition. Yet, how this impacts on establishment and maintenance of gene expression programs is not known. We hypothesize that chromatin replication represents a critical window for epigenetic cell memory and cell fate decisions, and predict that three histone-based processes play critical roles in guarding cell identity: 1) new histone deposition to regulate nucleosome occupancy and transcription factor (TF) binding, 2) accurate transmission of old modified histones by dedicated recycling machinery, and 3) recruitment of regulatory proteins to new and old histones to direct epigenome maintenance. To dissect these events mechanistically and test causal roles in cell fate decisions, we have set up a research program integrating explorative proteomics and histone chaperone structure-function analysis with stem cell biology and new cutting-edge genomic tools developed by my research group. We have identified novel mechanisms in chromatin assembly and histone inheritance, and revealed that inheritance of histone modifications plays a critical role maintaining normal genome regulation and supporting embryonic differentiation.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We have discovered that MCM2, part of the replicative helicase, is responsible for segregation of parental histones to lagging strand and ensuring balanced transmission of histone post-translational modifications (PTMs) to both DNA strands (Petryk et al., 2018, Science). Using mouse ES cells expressing MCM2 histone binding mutants as a powerful and unique tool, we have revealed a critical role of histone-based inheritance in genome regulation and cell fate decisions.
We have uncovered a new histone chaperone DNAJC9 and identified its dual functionality as a molecular chaperone and histone chaperone that facilitates histone transactions in different cellular environments (Hammond et al., 2021, Mol Cell). This work demonstrates that heat shock molecular chaperones support histone supply chains from synthesis to deposition.
In a structure-function study of the NASP histone chaperone, we characterize two distinct histone binding modes and reveal the molecular basis for how NASP protects soluble histones from degradation (Bao, Carraro et al., Nucleic Acis Res 2022).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Our research has provided a major advance in understanding epigenetic cell memory by 1) identifying novel mechanisms of histone chaperoning and deposition, and 2) addressing how the inheritance of histone modifications during DNA replication impacts gene regulation and cell fate decisions.

Figure for publishable summary