Concentric organization of A- and B-type lamins predicts their distinct roles in the spatial organization and stability of the nuclear lamina

Nmezi, Bruce; Xu, Jianquan; Fu, Rao; Armiger, Travis J.; Rodríguez-Bey, Guillermo; Powell, Juliana S.; Ma, Hongqiang; Sullivan, Mara; Tu, Yiping; Chen, Natalie; Young, Stephen G.; Stolz, Donna B.; Dahl, Kris Noel; Liu, Yang; Padiath, Quasar Saleem

doi:10.1073/pnas.1810070116

Cited by 119 publications

(131 citation statements)

References 47 publications

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“…In order to test this hypothesis, it is necessary to explore the space-time compaction and accessibility of CDs. Super-resolved fluorescence microscopy, including single molecule localization microscopy (SMLM) and stochastic optical reconstruction microscopy (STORM), may become the methods of choice to measure absolute differences of DNA/chromatin compaction with spatial resolution at the nanometer scale [79, 84, 85], whereas chromatin accessibility can be probed indirectly with methods that allow to measure molecular diffusion rates [86–89].…”

Section: Discussionmentioning

confidence: 99%

Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

Cremer

Brandstetter

Maiser

et al. 2019

Preprint

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43The human genome forms thousands of "contact domains", which are intervals of enhanced 44 contact frequency. Some, called "loop domains" are thought to form by cohesin-mediated loop 45 extrusion. Others, called "compartmental domains", form due to the segregation of active and 46 inactive chromatin into A and B compartments. Recently, Hi-C studies revealed that the 47 depletion of cohesin leads to the disappearance of all loop domains within a few hours, but 48 strengthens compartment structure. Here, we combine live cell microscopy, super-resolution 49 microscopy, Hi-C, and studies of replication timing to examine the longer-term consequences 50 of cohesin degradation in HCT-116 human colorectal carcinoma cells, tracking cells for up to 51 30 hours. Surprisingly, cohesin depleted cells proceed through an aberrant mitosis, yielding a 52 single postmitotic cell with a multilobulated nucleus. Hi-C reveals the continued disappearance 53 of loop domains, whereas A and B compartments are maintained. In line with Hi-C, microscopic 54 observations demonstrate the reconstitution of chromosome territories and chromatin 55 domains. An interchromatin channel system (IC) expands between chromatin domain clusters 56 and carries splicing speckles. The IC is lined by active chromatin enriched for RNA Pol II and 57 depleted in H3K27me3. Moreover, the cells exhibit typical early-, mid-, and late-DNA 58 replication timing patterns. Our observations indicate that the functional nuclear 59 compartmentalization can be maintained in cohesin depleted pre-and postmitotic cells.60 However, we find that replication foci -sites of active DNA synthesis -become physically 61 larger consistent with a model where cohesin dependent loop extrusion tends to compact 62 intervals of replicating chromatin, whereas their genomic boundaries are associated with 63 compartmentalization, and do not change.64 65 3 Abbreviations 66 3D FISH = 3D fluorescence in situ hybridization 67 3D SIM = 3D structured illumination microscopy 68 AID = auxin inducible degron 69 ANC / INC = active / inactive nuclear compartment 70 CT = chromosome territory 71 CD(C) = chromatin domain (cluster) 72 CTCF = CCCTC binding factor 73 DAPI = 4',6-diamidino-2-phenylindole 74 EdU = 5-Ethynyl-2'-deoxyuridine 75 Hi-C = chromosome conformation capturing combined with deep sequencing 76 IC = interchromatin compartment 77 MLN = multilobulated nucleus 78 NC = nucleosome cluster 79 PBS = phosphate buffered saline 80 PBST = phosphate buffered saline with 0.02% Tween 81 PR = perichromatin region 82 RD = replication domain 83 RL = replication labeling 84 TAD = topologically associating domain 85 86 109 strengthened, leading to the presence of compartment domains and even compartment loops110 (but no loop domains) in the treated cells [18]. Other studies, using different cell types and 111 approaches for cohesin elimination yielded similar results [19-21], (reviewed in [22]). 112Here, we study the longer-term consequences of cohesin depletion and its effects on 113 the higher order nuclear a...

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Section: Discussionmentioning

confidence: 99%

Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

Cremer

Brandstetter

Maiser

et al. 2019

Preprint

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“…B‐type lamins result from expression of two distinct genes, namely LMNB1 and LMNB2, originating lamin B1 and B2 isoforms, respectively. Interestingly, while the B‐type lamins form a looser network closely associated with the INM, the A‐type lamins’ network is more tightly spaced and remain in proximity to the INM facing the nucleoplasm (Delbarre et al, 2006; Goldberg, Huttenlauch, Hutchison, & Stick, 2008; Nmezi et al, 2019; Shimi et al, 2008, 2015; Xie et al, 2016). Another interesting aspect is that the lamins bind directly to chromatin via the lamina‐associated domains (LADs).…”

Section: Introductionmentioning

confidence: 99%

Nuclear envelope dysfunction and its contribution to the aging process

et al. 2020

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The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins’ alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina‐associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process.

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“…A prediction based on this difference in the lamina incorporation pathways is that Lamin A and B-type Lamins build the foundation of the nuclear lamina meshwork, on which Lamin C meshwork assembles. While exact localization of Lamin C within the nuclear lamina has not yet been defined, a recent study using super-resolution microscopy reported that localization of Lamin A/C (detected by an antibody recognizing both Lamin A and C) is closer to the nuclear interior than Lamin B1 within the nuclear lamina meshwork [ 67 ]. Thus, one possibility is that Lamin C is most accessible by kinases of all lamin subtypes within the nuclear lamina by virtue of their differential localization within the nuclear lamina.…”

Section: Nuclear Lamin Phosphorylation In Interphasementioning

confidence: 99%

Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies

Liu

Ikegami

2020

Nucleus

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Decades of studies have established that nuclear lamin polymers form the nuclear lamina, a protein meshwork that supports the nuclear envelope structure and tethers heterochromatin to the nuclear periphery. Much less is known about unpolymerized nuclear lamins in the nuclear interior, some of which are now known to undergo specific phosphorylation. A recent finding that phosphorylated lamins bind gene enhancer regions offers a new hypothesis that lamin phosphorylation may influence transcriptional regulation in the nuclear interior. In this review, we discuss the regulation, localization, and functions of phosphorylated lamins. We summarize kinases that phosphorylate lamins in a variety of biological contexts. Our discussion extends to laminopathies, a spectrum of degenerative disorders caused by lamin gene mutations, such as cardiomyopathies and progeria. We compare the prevailing hypothesis for laminopathy pathogenesis based on lamins’ function at the nuclear lamina with an emerging hypothesis based on phosphorylated lamins’ function in the nuclear interior.

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Concentric organization of A- and B-type lamins predicts their distinct roles in the spatial organization and stability of the nuclear lamina

Cited by 119 publications

References 47 publications

Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

Cohesin depleted cells rebuild functional nuclear compartments after endomitosis

Nuclear envelope dysfunction and its contribution to the aging process

Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies

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