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Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation.

ABSTRACT: The three-dimensional organization of chromosomes within the nucleus and its dynamics during differentiation are largely unknown. To visualize this process in molecular detail, we generated high-resolution maps of genome-nuclear lamina interactions during subsequent differentiation of mouse embryonic stem cells via lineage-committed neural precursor cells into terminally differentiated astrocytes. This reveals that a basal chromosome architecture present in embryonic stem cells is cumulatively altered at hundreds of sites during lineage commitment and subsequent terminal differentiation. This remodeling involves both individual transcription units and multigene regions and affects many genes that determine cellular identity. Often, genes that move away from the lamina are concomitantly activated; many others, however, remain inactive yet become unlocked for activation in a next differentiation step. These results suggest that lamina-genome interactions are widely involved in the control of gene expression programs during lineage commitment and terminal differentiation.

SUBMITTER: Peric-Hupkes D

PROVIDER: S-EPMC5975946 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation.

Peric-Hupkes Daan D Meuleman Wouter W Pagie Ludo L Bruggeman Sophia W M SW Solovei Irina I Brugman Wim W Gräf Stefan S Flicek Paul P Kerkhoven Ron M RM van Lohuizen Maarten M Reinders Marcel M Wessels Lodewyk L van Steensel Bas B

Molecular cell 20100501 4

The three-dimensional organization of chromosomes within the nucleus and its dynamics during differentiation are largely unknown. To visualize this process in molecular detail, we generated high-resolution maps of genome-nuclear lamina interactions during subsequent differentiation of mouse embryonic stem cells via lineage-committed neural precursor cells into terminally differentiated astrocytes. This reveals that a basal chromosome architecture present in embryonic stem cells is cumulatively a ...[more]

PMID: 20513434

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Project description:The three-dimensional organization of chromosomes within the nucleus and its dynamics during differentiation are largely unknown. We present a genome-wide analysis of the interactions between chromatin and the nuclear lamina during differentiation of mouse embryonic stem cells (ESCs) into lineage-committed neural precursor cells (NPCs) and terminally differentiated astrocytes. Chromatin in each of these cell types shows a similar organization into large lamina associated domains (LADs), which represent a transcriptionally repressive environment. During sequential differentiation steps, lamina interactions are progressively modified at hundreds of genomic locations. This remodeling is typically confined to individual transcription units and involves many genes that determine cellular identity. From ESCs to NPCs, the majority of genes that move away from the lamina are concomitantly activated. Strikingly, a significant amount remain inactive yet become primed for activation by further differentiation. These results suggest that lamina-genome interactions are widely involved in the control of gene expression programs during lineage commitment and terminal differentiation. UPDATE WM20121119: We have added per-probe Hidden Markov Model state calls for the 4 cell types. These calls are not used in Peric-Hupkes, Meuleman et al. (2010), but are used in Meuleman, Peric-Hupkes et al. (2012). The procedure to arrive at this HMM state calls is as follows: We fitted a two-state HMM whereby emissions are distributed as Student's t variables. Mean and variance of DamID signals differ between states, but the degree of freedom (nu) is the same. Gaps in the probe coverage were filled by evenly spaced null probe-values. The parameters were estimated by an adaptation of the ECME algorithm to the HMM framework, showing faster convergence than regular EM when nu is unknown (Filion et al., Cell, 2010). State calls were derived through the Viterbi algorithm. This process was repeated separately for each cell type, yielding per-probe calls. Probes in the ‘bound’ (1) state are indicated as LAD-probes, probes in the ‘unbound’ (0) state as inter-LAD-probes. UPDATE WM20130301: We have also added (1-based) BED files of constitutive LAD and inter-LAD regions (mm9) across the 4 cell types. These regions are the result of simply concatenating directly adjacent cLAD/ciLAD Hidden Markov Model state calls. Again, these calls are not used in Peric-Hupkes, Meuleman et al. (2010), but are used in Meuleman, Peric-Hupkes et al. (2012).

Dataset Information

Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation.

Publications

Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation.

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