Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction

Abstract

Summary Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin and, independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.

A Lamina-Associated Domain Border Governs Nuclear Lamina Interactions, Transcription, and Recombination of the Tcrb Locus

“…Histone H3 lysine 9 dimethylation (H3K9me2) is enriched at the nuclear periphery and overlaps with LADs genome-wide (Kind et al, 2013; Peric-Hupkes et al, 2010; Poleshko et al, 2017; Wen et al, 2009). Disruption of the methyltransferases that deposit H3K9me2 by knockdown or inhibition has been shown to cause genes in LADs to move away from the nuclear periphery (Bian et al, 2013; Harr et al, 2015; Kind et al, 2013; Towbin et al, 2012).…”

“…usRC has a similar organization and our functional dissection of this LAD border indicates that the CBEs and promoter elements cooperate to mediate LAD border activity. LADs have been shown to be enriched for H3K9me2 along their entire length, and this modification is thought to be essential for anchoring to the NL (Harr et al, 2015; Kind et al, 2013; Peric-Hupkes et al, 2010; Poleshko et al, 2017; Towbin et al, 2012; Wen et al, 2009). Our analysis of wild-type VL3-3M2 cells confirmed the correlation between DamID and H3K9me2 signals, both genome-wide and at the Tcrb locus.…”

“…LADs have a lower gene density than non-LADs, and genes within LADs are either transcriptionally inactive or expressed at lower levels than non-LAD genes (Guelen et al, 2008; Peric-Hupkes et al, 2010). Transcriptional suppression at the NL is mediated directly, by repressors like heterochromatin protein 1 (HP1) and histone deacetylase 3 (HDAC3), which interact with the NL or NL-associated proteins (Poleshko et al, 2017; Polioudaki et al, 2001; Somech et al, 2005; Zullo et al, 2012), and indirectly, by the exclusion of transcription factors and transcriptional machinery from the nuclear periphery (Yao et al, 2011). …”

Reactions Coupled Self‐ and Co‐Assembly: A Highly Dynamic Process and the Resultant Spatially Inhomogeneous Structure

“…[5][6][7][8] The complexity includes not only the hierarchical structures throughout all length scales, but also their highly dynamic adaptiont ot he environments.T he representative example is the stem cells, which can develop into differentt issues or organs depending on the environments. [9][10][11][12] It is highly important to develop artificial systems that can develop into different structures from the same startingm aterials upon the change of environments to help to understand such mystery phenomenona nd construct artificial intelligent systems. It has to be mentioned that the highly adaptive systemsh ere have inherentd ifferences from the ubiquitous systems in which different conditions lead to different products.…”

Mechanical property characterization of hundreds of single nuclei based on microfluidic constriction channel

“…Nuclear lamina consisting of lamins and nuclear lamin‐associated membrane proteins is a fibrillar network structure that exists in the nucleus of most eukaryotic cells . Such a fibrillar network structure of nuclear lamina connects the inner nuclear membrane inside a nucleus, and the endoplasmic reticulum in cytoplasm not only providing the mechanical support of nucleus , but also involving several cellular events [e.g., chromatin organization , cell cycle regulation , cell differentiation , DNA replication ]. Reports in literature have demonstrated that the variations of mechanical properties of nuclei are associated with physiological and pathological status of cells including tumor development , stem cell differentiation , and blood cell relevant diseases .…”