Chromatin Structure from Development to Ageing

Ayala-Guerrero, Lorelei; Claudio-Galeana, Sherlyn; Furlan-Magaril, Mayra; Castro-Obregón, Susana

doi:10.1007/978-3-031-21410-3_2

Cited by 2 publications

(4 citation statements)

References 201 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, a greater variability of the chromatin radial distribution in proventriculus nuclei of the Drosophila Lamin mutants in comparison to WT nuclei can be observed by comparing three experimental groups ( [ 119 ]). Thus, a dramatic loss or dysfunction of lamins during aging or disease [ 49 , 62 - 64 , 144 ] may contribute to the increased disorder in gene expression due to greater variability of the global chromatin architecture predicted in this work.…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, attractions between heterochromatic TADs emerged as the main force of compartmentalization, while LAD–NE interactions are crucial for controlling the global spatial morphology of the nucleus [ 54 , 55 , 57 ]. However, a number of questions remains unanswered, related to sensitivity of the general organization principles with respect to global loss of chromatin–lamina interactions, which may occur in disease or senescence [ 52 , 61 - 64 ]. Also, the strength of TAD–TAD interactions can naturally vary during life of organisms.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Tolokh

Kinney

Sharakhov

et al. 2023

Epigenetics & Chromatin

View full text Add to dashboard Cite

Background Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of three-dimensional (3D) chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult. Results We have developed a coarse-grained dynamical model of D. melanogaster nuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD–NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. The simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development. Predicted positioning of all LADs at the NE is highly dynamic—the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome, which also has the same strong effect on the predicted positioning of individual TADs -- higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD–TAD interactions compared to the lamin depleted nuclei, where a small (0.5 kT) increase of cross-type TAD–TAD interactions doubles the chromatin density in the central nucleus region. Conclusions A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD–NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD–TAD interactions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Tolokh

Kinney

Sharakhov

et al. 2023

Epigenetics & Chromatin

View full text Add to dashboard Cite

show abstract

“…In fact, a greater variability of the chromatin radial distribution in proventriculus nuclei of the Drosophila Lamin mutants in comparison to WT nuclei can be observed by comparing three experimental groups ([117]). Thus, a dramatic loss or dysfunction of lamins during aging or disease [48, 138, 61, 62, 63] may contribute to the increased disorder in gene expression due to greater variability of the global chromatin architecture predicted in this work.…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, attractions between heterochromatic TADs emerged as the main force of compartmentalization, while LAD-NE interactions are crucial for controlling the global spatial morphology of the nucleus [54, 56, 53]. However, a number of questions remains unanswered, related to sensitivity of the general organization principles with respect to global loss of chromatin-lamina interactions, which may occur in disease or senescence [51, 60, 61, 62, 63]. Also, the strength of TAD-TAD interactions can naturally vary during life of organisms.…”

Section: Introductionmentioning

confidence: 99%

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Tolokh

Kinney

Sharakhov

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: Interactions between topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of 3D chromatin structure and dynamics at the level of the entire nucleus; however, a full quantitative picture is still lacking. Relevant genome-wide experiments that may provide statistically significant conclusions remain difficult. Results: We have developed a coarse-grained dynamic model of the Drosophila melanogaster nucleus at TAD (about 100 kb) resolution that explicitly accounts for four distinct epigenetic classes of TADs and describes time evolution of the chromatin over the entire interphase. Best agreement with experiment is achieved when the simulation includes an entire biological system - an ensemble of complete nuclei, corresponding to the experimentally observed set of mutual arrangements of chromosomes, properly weighted according to experiment. The model is validated against multiple experiments, including those that describe changes in chromatin induced by lamin depletion. Predicted positioning of LADs at the NE is highly dynamic (mobile) - the same LAD can attach, detach, and re-attach itself to the NE multiple times during interphase. The average probability of a LAD to be found at the NE varies by an order of magnitude, determined by the highly variable local density of nearby LADs along the genome. The distribution of LADs along the genome has a strong effect on the average radial positioning of individual TADs, playing a notable role in maintaining a non-random average global structure of chromatin. Predicted sensitivity of fruit fly chromatin structure to the balance between TAD-TAD and LAD-NE interactions, also observed previously in models of mammalian chromosomes, suggests conservation of this principle of chromatin organisation across species of higher eukaryotes. Reduction of LAD-NE affinity weakly affects local chromatin structure, as seen in the model-derived Hi-C maps, however, its wild-type strength substantially reduces sensitivity of the chromatin density distribution to variations in the strength of TAD-TAD interactions. Conclusions: A dynamical model of the entire 3D fruit fly genome makes multiple genome-wide predictions of biological interest. We conjecture that one important role of LADs and their attractive interactions with the NE is to create the average global chromatin structure and stabilize it against inevitable cell-to-cell variations of TAD-TAD interactions.

show abstract

Chromatin Structure from Development to Ageing

Cited by 2 publications

References 201 publications

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Contact Info

Product

Resources

About