Daphne S Cabianca, Celia Muñoz-Jiménez, Véronique Kalck, Dimos Gaidatzis, Jan Padeken, Andrew Seeber, Peter Askjaer, and Susan M Gasser. 2019. “
Active chromatin marks drive spatial sequestration of heterochromatin in C. elegans nuclei.” Nature, 569, 7758, Pp. 734-739.
AbstractThe execution of developmental programs of gene expression requires an accurate partitioning of the genome into subnuclear compartments, with active euchromatin enriched centrally and silent heterochromatin at the nuclear periphery. The existence of degenerative diseases linked to lamin A mutations suggests that perinuclear binding of chromatin contributes to cell-type integrity. The methylation of lysine 9 of histone H3 (H3K9me) characterizes heterochromatin and mediates both transcriptional repression and chromatin anchoring at the inner nuclear membrane. In Caenorhabditis elegans embryos, chromodomain protein CEC-4 bound to the inner nuclear membrane tethers heterochromatin through H3K9me, whereas in differentiated tissues, a second heterochromatin-sequestering pathway is induced. Here we use an RNA interference screen in the cec-4 background and identify MRG-1 as a broadly expressed factor that is necessary for this second chromatin anchor in intestinal cells. However, MRG-1 is exclusively bound to euchromatin, suggesting that it acts indirectly. Heterochromatin detachment in double mrg-1; cec-4 mutants is rescued by depleting the histone acetyltransferase CBP-1/p300 or the transcription factor ATF-8, a member of the bZIP family (which is known to recruit CBP/p300). Overexpression of CBP-1 in cec-4 mutants is sufficient to delocalize heterochromatin in an ATF-8-dependent manner. CBP-1 and H3K27ac levels increase in heterochromatin upon mrg-1 knockdown, coincident with delocalization. This suggests that the spatial organization of chromatin in C. elegans is regulated both by the direct perinuclear attachment of silent chromatin, and by an active retention of CBP-1/p300 in euchromatin. The two pathways contribute differentially in embryos and larval tissues, with CBP-1 sequestration by MRG-1 having a major role in differentiated cells.
O Shukron, A Seeber, A Amitai, and D Holcman. 2019. “
Advances Using Single-Particle Trajectories to Reconstruct Chromatin Organization and Dynamics.” Trends Genet, 35, 9, Pp. 685-705.
AbstractChromatin organization remains complex and far from understood. In this article, we review recent statistical methods of extracting biophysical parameters from in vivo single-particle trajectories of loci to reconstruct chromatin reorganization in response to cellular stress such as DNA damage. We look at methods for analyzing both single locus and multiple loci tracked simultaneously and explain how to quantify and describe chromatin motion using a combination of extractable parameters. These parameters can be converted into information about chromatin dynamics and function. Furthermore, we discuss how the timescale of recurrent encounter between loci can be extracted and interpreted. We also discuss the effect of sampling rate on the estimated parameters. Finally, we review a polymer method to reconstruct chromatin structure using crosslinkers between chromatin sites. We list and refer to some software packages that are now publicly available to simulate polymer motion. To conclude, chromatin organization and dynamics can be reconstructed from locus trajectories and predicted based on polymer models.
Roxanne Oshidari, Karim Mekhail, and Andrew Seeber. 2019. “
Mobility and Repair of Damaged DNA: Random or Directed?” Trends Cell Biol.
AbstractThe increased mobility of damaged DNA within the nucleus can promote genome stability and cell survival. New cell biology approaches have indicated that damaged DNA mobility exhibits random and directed movements during DNA repair. Here, we review recent studies that collectively reveal that cooperation between different molecular mechanisms, which underlie increases in the random and directional motion of damaged DNA, can promote genome repair. We also review the latest approaches that can be used to distinguish between random and directed motions of damaged DNA or other biological molecules. Detailed understanding of the mechanisms behind the increased motion of damaged DNA within the nucleus will reveal more of the secrets of genome organization and stability while potentially pointing to novel research and therapeutic tools.