Histones and histone modifications in perinuclear chromatin anchoring: from yeast to man

Abstract

It is striking that within a eukaryotic nucleus, the genome can assume specific spatiotemporal distributions that correlate with the cell's functional states. Cell identity itself is determined by distinct sets of genes that are expressed at a given time. On the level of the individual gene, there is a strong correlation between transcriptional activity and associated histone modifications. Histone modifications act by influencing the recruitment of non-histone proteins and by determining the level of chromatin compaction, transcription factor binding, and transcription elongation. Accumulating evidence also shows that the subnuclear position of a gene or domain correlates with its expression status. Thus, the question arises whether this spatial organization results from or determines a gene's chromatin status. Although the association of a promoter with the inner nuclear membrane (INM) is neither necessary nor sufficient for repression, the perinuclear sequestration of heterochromatin is nonetheless conserved from yeast to man. How does subnuclear localization influence gene expression? Recent work argues that the common denominator between genome organization and gene expression is the modification of histones and in some cases of histone variants. This provides an important link between local chromatin structure and long-range genome organization in interphase cells. In this review, we will evaluate how histones contribute to the latter, and discuss how this might help to regulate genes crucial for cell differentiation.

Keywords: CEC‐4; histone methylation; inner nuclear membrane; nuclear envelope; nuclear organization.

Figure 1. Chromatin distribution changes occur upon cell differentiation

In differentiated cells, there are distinct domains of dark‐staining heterochromatin at the nuclear periphery and around the nucleolus. Tissue‐specific genes are found in heterochromatic zones when repressed and are in euchromatic zones when active. This is true in many species.

Figure 2. Anchoring chromatin to the nuclear periphery in mammalian cells

As mammalian cells differentiate, additional domains become associated with the nuclear lamina, called variable LADs (vLADs). These changes between cell types are enriched in cell type‐specific genes and are often found at the edges of LADs. (A) vLAD anchoring mechanisms. Borders of vLADs are enriched for both H3K9me2/3 and H3K27me3 and shift to the nuclear periphery in a manner dependent on PRC2 activity as well as on Suv39H1 and G9a. (B) Mechanisms implicated in the anchoring of constitutive/common LADs. They depend on H3K9 methylation deposited by G9a and Suv39h and involve ligands which may include HP1 and other unknown methylation readers. Transcription factor interactions with INM proteins, such as the cKrox (zbtb7b)/HDAC3/Lap2β bridge, may also be relevant for tissue‐specific LADs.

Figure 3. Anchoring chromatin to the nuclear periphery in Caenorhabditis elegans

In C. elegans early embryos, CEC‐4 is a H3K9me1, me2, or me3 ligand that mediates anchoring to the nuclear periphery, without necessarily repressing transcription. The H3K9me ligands, HPL1, HPL2, and LIN‐61, mediate transcriptional repression by binding H3K9 methylation, but do not anchor chromatin. SET‐25 recognizes the H3K9me3‐containing chromatin that it creates and together with HP1 homologs and LIN‐61 leads to repression. In differentiated cells, alternative anchors may be present.

Figure 4. Anchoring heterochromatin in budding and fission yeast

(A) In budding yeast, telomere anchoring occurs in both a silencing‐dependent and a silencing‐independent manner. At telomeric repeats, Sir4 binds Rap1 and/or yKU to mediate interaction with Esc1, an INM protein. At subtelomeric nucleosomes, Sir4 binds as part of the repressive SIR2‐3‐4 complex to silence chromatin. Sir2 deacetylates to allow for Sir3 binding. Sir3 and Sir4 interact. This mediates interaction with Esc1. Interaction of Sir4 with yKU can mediate interaction with a SUN domain protein, Mps3 (reviewed in 116). Interaction with Nup170 has also been reported 117. (B) In fission yeast, Lem2 has distinct N‐terminal LEM and C‐terminal MSC domains 108. LEM2 cooperates with the RNAi machinery assembly factor Dsh1 to anchor telomeres (not shown), and with the centromere factor Csi1 to cluster centromeric heterochromatin at the SPB, which is anchored through the SUN domain protein Sad1. The MSC domain contributes to pericentric heterochromatin through still unclear mechanisms, but silencing and anchoring can be separated. At telomeres, anchoring and silencing are not separated by mutation of either LEM or MSC domains 109. Silencing acts through the SHREC complex. Telomeres have alternative pathways of anchoring which include Fft3 and telomeric repeat binding factors Taz1 (see text). (B) is derived from a model in 109.