Lamins Organize the Global Three-Dimensional Genome from the Nuclear Periphery

Zheng, Xiaobin; Hu, Jiabiao; Yue, Sibiao; Kristiani, Lidya; Kim, Miri; Sauria, Michael E.G.; Taylor, James; Kim, Young-Jo; Zheng, Yixian

doi:10.1016/j.molcel.2018.05.017

Cited by 159 publications

(157 citation statements)

References 58 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Lamins are known to influence the expression of genes found both in the lamina‐associated chromatin domains (LADs) and in the non‐LADs. Our recent studies of lamin null mouse embryonic stem cells (mESCs) have shown that lamins regulate the 3D chromatin organization by ensuring the proper condensation and position of LADs at the nuclear periphery (Zheng et al, ). The de‐condensation and detachment of LADs upon lamin loss can lead to altered gene expression by bringing the active chromatin domains into the close vicinity of inactive ones.…”

Section: Discussionmentioning

confidence: 99%

Cell‐type‐specific role of lamin‐B1 in thymus development and its inflammation‐driven reduction in thymus aging

Yue

Zheng

2019

Aging Cell

Self Cite

View full text Add to dashboard Cite

Cellular architectural proteins often participate in organ development and maintenance. Although functional decay of some of these proteins during aging is known, the cell‐type‐specific developmental role and the cause and consequence of their subsequent decay remain to be established especially in mammals. By studying lamins, the nuclear structural proteins, we demonstrate that lamin‐B1 functions specifically in the thymic epithelial cells (TECs) for proper thymus organogenesis. An up‐regulation of proinflammatory cytokines in the intra‐thymic myeloid immune cells during aging accompanies a gradual reduction of lamin‐B1 in adult TECs. We show that these cytokines can cause senescence and lamin‐B1 reduction of the young adult TECs. Lamin‐B1 supports the expression of TEC genes that can help maintain the adult TEC subtypes we identified by single‐cell RNA‐sequencing, thymic architecture, and function. Thus, structural proteins involved in organ building and maintenance can undergo inflammation‐driven decay which can in turn contribute to age‐associated organ degeneration.

show abstract

Section: Discussionmentioning

confidence: 99%

Cell‐type‐specific role of lamin‐B1 in thymus development and its inflammation‐driven reduction in thymus aging

Yue

Zheng

2019

Aging Cell

Self Cite

View full text Add to dashboard Cite

show abstract

“…Various models of lamin association with LADs have been proposed, including direct tethering to chromatin domains ( Gonzalez-Sandoval et al 2015) and a 'meshwork caging model' where the dense lamin network traps chromatin domains (Amendola and Steensel 2015;Kim, Zheng, and Zheng 2019). Work in Lamin null (Lamin B1, B1 and A triple knockout) mice demonstrated that loss of LADs altered chromatin organisation and affected gene expression in neighbouring 'non-LAD' genomic regions (Zheng et al 2018). Interestingly, murine skin develops normally without Lamin B1 or B2 expression (Yang et al 2011) and…”

Section: Discussionmentioning

confidence: 99%

Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

Rogerson

Wotherspoon

O'Shaughnessy

2019

Preprint

View full text Add to dashboard Cite

Keratinocyte cornification and epidermal barrier formation are tightly controlled processes, which require complete degradation of intracellular organelles, including removal of keratinocyte nuclei. Keratinocyte nuclear destruction requires Akt1-dependent phosphorylation and degradation of the nuclear lamina protein, Lamin A/C, essential for nuclear integrity. However, the molecular mechanisms that result in complete nuclear removal and their regulation are not well defined. Post-confluent cultures of rat epidermal keratinocytes (REKs) undergo spontaneous and complete differentiation, allowing visualisation and perturbation of the differentiation process in vitro. We demonstrate that there is dispersal of phosphorylated Lamin A/C to structures throughout the cytoplasm in differentiating keratinocytes. We show that the dispersal of phosphorylated Lamin A/C is Akt1-dependent and these structures are specific for the removal of Lamin A/C from the nuclear lamina; nuclear contents and Lamin B were not present in these structures.Immunoprecipitation identified a group of functionally related Akt1 target proteins involved in Lamin A/C dispersal, including actin, which forms cytoskeletal microfilaments, Arp3, required for actin filament nucleation, and Myh9, a component of myosin IIa, a molecular motor that can translocate along actin filaments. Disruption of actin filament polymerisation, nucleation or myosin IIa activity prevented formation and dispersal of cytoplasmic Lamin A/C structures. Live imaging of keratinocytes expressing fluorescently tagged nuclear proteins showed a nuclear volume reduction step taking less than 40 minutes precedes final nuclear destruction. Preventing Akt1-dependent Lamin A/C phosphorylation and disrupting cytoskeletal Akt1associated proteins prevented nuclear volume reduction. Single cell RNA sequencing of differentiating keratinocytes identified gene changes correlated with lamin dispersal, which we propose are due to changes in lamina-associated domains upon Lamin A/C dispersal. We propose keratinocyte nuclear destruction and differentiation requires myosin II activity and the actin cytoskeleton for two intermediate processes: Lamin A/C dispersal and rapid nuclear volume reduction.

show abstract

“…The authors proposed that the role of lamin in LADs might be dependent on the cell type and that other components of the nuclear lamina might help to organize LADs (Amendola & Steensel, 2015). However, a more recent study reported decondensation or detachment of specific LAD regions from the nuclear periphery in lamin null mouse ESCs, which alters the chromatin domain interactions and transcription (Zheng et al, 2018). Additional studies indicated that lamins are essential for chromatin organization at early developmental stages (Melcer et al, 2012).…”

Section: Chromatin Organizationmentioning

confidence: 99%

Nuclear envelope dysfunction and its contribution to the aging process

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Lamins Organize the Global Three-Dimensional Genome from the Nuclear Periphery

Cited by 159 publications

References 58 publications

Cell‐type‐specific role of lamin‐B1 in thymus development and its inflammation‐driven reduction in thymus aging

Cell‐type‐specific role of lamin‐B1 in thymus development and its inflammation‐driven reduction in thymus aging

Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

Nuclear envelope dysfunction and its contribution to the aging process

Contact Info

Product

Resources

About