Nuclear organization and regulation of the differentiated state

Abstract

Regulation of the differentiated identity requires active and continued supervision. Inability to maintain the differentiated state is a hallmark of aging and aging-related disease. To maintain cellular identity, a network of nuclear regulators is devoted to silencing previous and non-relevant gene programs. This network involves transcription factors, epigenetic regulators, and the localization of silent genes to heterochromatin. Together, identity supervisors mold and maintain the unique nuclear environment of the differentiated cell. This review describes recent discoveries regarding mechanisms and regulators that supervise the differentiated identity and protect from de-differentiation, tumorigenesis, and attenuate forced somatic cell reprograming. The review focuses on mechanisms involved in H3K9me3-decorated heterochromatin and the importance of nuclear lamins in cell identity. We outline how the biophysical properties of these factors are involved in self-compartmentalization of heterochromatin and cell identity. Finally, we discuss the relevance of these regulators to aging and age-related disease.

Chemo-Mechanical Cues Modulate Nano-Scale Chromatin Organization in Healthy and Diseased Connective Tissue Cells

“…Conversely, and perhaps more surprisingly, when these same cells were placed on soft substrates, highly condensed chromatin domains relocalized to the nuclear periphery, a region in which constitutive heterochromatin resides and methyltransferases are abundant 16,29 . This nuclear periphery has long been considered as a transcriptionally repressive area 40 where inner nuclear membrane proteins in the nuclear lamina interact with proximal chromatin creating heterochromatin structures 41,42 . It has recently been suggested that this laminal sequestration at the nuclear envelope depends on specific epigenetic modifications, and indeed we observed that human MSCs on soft substrates increased their nano-scale H3K27me3 localization at the nuclear periphery.…”

Diversity of Nuclear Lamin A/C Action as a Key to Tissue-Specific Regulation of Cellular Identity in Health and Disease

“…On the other hand, genes required for specific differentiation are activated via detachment of genome regions from the nuclear lamina. These genome reorganizations are cell cycle stage-dependent, and vary in the different cells from different origins ( Bitman-Lotan and Orian, 2021 ; Shah et al, 2021 ).…”

“…It has been shown that heterochromatin is associated with lamin A/C forming the nuclear lamina, while euchromatin dominating in the nuclear interior is connected with a small number of nucleoplasmic lamin A/C. A-type lamins are considered to regulate the repressive state of genes included in facultative heterochromatin ( Gruenbaum and Foisner, 2015 ; de Leeuw et al, 2018 ; Bitman-Lotan and Orian, 2021 ). This three-dimensional organization of chromatin contributes to the gene expression regulation and maintenance of silencing of heterochromatic genes.…”

“…Thus, genes non-relevant to differentiation interact with lamina and become silent. At the same time, differentiation-related genes unattached from lamina are available for their expression, facilitating the development of a particular cell identity ( Bitman-Lotan and Orian, 2021 ).…”

“…Active gene expression is associated with releasing LADs from the nuclear lamina. In contrast, inactivation of expression is associated with the attachment of LADs to the lamina ( Briand and Collas, 2020 ; Bitman-Lotan and Orian, 2021 ; Shah et al, 2021 ).…”