Wei Y et al. (2014) Hum Reprod Update "Environmental epigenetic inheritance through gametes and implications for human reproduction."

Sun QY, Wei Y, Schatten H

[Hum Reprod Update, 2014]

BACKGROUND: Traditional studies focused on DNA as the heritable information carrier that passes the phenotype from parents to offspring. However, increasing evidence suggests that information, that is independent of the DNA sequence, termed epigenetic information, can be inherited between generations. Recently, in our lab, we found that prediabetes in fathers increases the susceptibility to diabetes in offspring through gametic cytosine methylation changes. Paternal prediabetes changed overall methylation patterns in sperm, and a large portion of differentially methylated loci can be transmitted to pancreatic islets of offspring up to the second generation. In this review, we survey the extensive examples of environmentally induced epigenetic inheritance in various species, ranging from Caenorhabditis elegans to humans. We focus mainly on elucidating the molecular basis of environmental epigenetic inheritance through gametes, which is an emerging theme and has important implications for explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases, which is also important for understanding the influence of environmental exposures on reproductive and overall health in offspring. METHODS: For this review, we included relevant data and information obtained through a PubMed database search for all English language articles published up to August 2014 which included the term 'environmental epigenetic inheritance' and 'transgenerational epigenetic inheritance'. We focused on research papers using animal models including Drosophila, C. elegans, mouse and rat. Human data were also included. RESULTS: Evidence from animal models suggests that environmental epigenetic inheritance through gametes exists in various species. Extensive molecular evidence suggests that epigenetic information carriers including DNA methylation, non-coding RNAs and chromatin proteins in gametes play important roles in the transmission of phenotypes from parents to offspring. CONCLUSIONS: Given the large number of experimental evidence from various organisms, it is clear that parental environmental alterations can affect the phenotypes of offspring through gametic epigenetic alterations. This more recent thinking based on new data may have implications in explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases. This also implies that, in the near future, epigenetic factors which are heritable should be regarded important in determining the risk of certain diseases. Moreover, identification of epigenetic markers in gametes (polar body or sperm) may hold great promise for predicting susceptibility to and preventing certain non-genetic diseases in offspring, as well as providing indications on parental environmental exposures.

Cain NE et al. (2015) Nucleus "SUN proteins and nuclear envelope spacing."

Cain NE, Starr DA

[Nucleus, 2015]

The nuclear envelope consists of 2 membranes separated by 30-50 nm, but how the 2 membranes are evenly spaced has been an open question in the field. Nuclear envelope bridges composed of inner nuclear membrane SUN proteins and outer nuclear membrane KASH proteins have been proposed to set and regulate nuclear envelope spacing. We tested this hypothesis directly by examining nuclear envelope spacing in Caenorhabditis elegans animals lacking UNC-84, the sole somatic SUN protein. SUN/KASH bridges are not required to maintain even nuclear envelope spacing in most tissues. However, UNC-84 is required for even spacing in body wall muscle nuclei. Shortening UNC-84 by 300 amino acids did not narrow the nuclear envelope space. While SUN proteins may play a role in maintaining nuclear envelope spacing in cells experiencing forces, our data suggest they are dispensable in most cells.

Zhou K et al. (2010) Dev Dyn "Movers and shakers or anchored: Caenorhabditis elegans nuclei achieve it with KASH/SUN."

Zhou K, Hanna-Rose W

[Dev Dyn, 2010]

The invariant cell division patterns that characterize Caenorhabditis elegans development make it an ideal system to study the mechanisms that control nuclear movement and positioning. Forward genetic screens in this system allowed identification of the key molecular machinery for connecting the nucleus to the cytoskeleton; pairs of protein partners, consisting of a KASH domain protein and a SUN domain protein, bridge the nuclear envelope to connect the nucleus to cytoskeletal components. The C. elegans genome encodes several KASH/SUN pairs, and mutant phenotypes as well as tissue-specific expression patterns suggest a diversity of functions. These functions include moving the nucleus but have been extended to effects on the chromosomes inside the nucleus as well. We review the impact of the C. elegans system in pioneering this field as well as the functions of these KASH/SUN protein pairs across spatial and temporal C. elegans development.

Horn HF (2014) Curr Top Dev Biol "LINC complex proteins in development and disease."

Horn HF

[Curr Top Dev Biol, 2014]

The LINC complex spans the nuclear envelope and plays critical roles in coordinating nuclear and cytoplasmic activities and in organizing nuclear and cytoskeletal features. LINC complexes are assembled from KASH and SUN-domain proteins, which interact in the nuclear envelope and form a physical link between the cytoskeleton and the nuclear interior. A number of diseases have been associated with mutations in genes coding for LINC complex proteins. Mouse models of LINC complex protein have provided valuable insight into LINC complex functions and into how these proteins contribute to the various diseases with which they have been associated.

Starr DA et al. (2003) J Cell Sci "ANChors away: an actin based mechanism of nuclear positioning."

Han M, Starr DA

[J Cell Sci, 2003]

Mechanisms for nuclear migration and nuclear anchorage function together to control nuclear positioning. Both tubulin and actin networks play important roles in nuclear positioning. The actin cytoskeleton. has been shown to position nuclei in a variety of systems from yeast to plants and animals. It can either act as a stable skeleton to anchor nuclei or supply the active force to move nuclei. Two C elegans genes and their homologues play important roles in these processes. Syne/ANC-1 anchors nuclei by directly tethering the nuclear envelope to the actin cytoskeleton, and UNC-84/SUN functions at the nuclear envelope to recruit Syne/ANC-1.

Wilhelmsen K et al. (2006) J Cell Sci "KASH-domain proteins in nuclear migration, anchorage and other processes."

Wilhelmsen K, Truong H, Ketema M, Sonnenberg A

[J Cell Sci, 2006]

The nucleus in eukaryotic cells can move within the cytoplasm, and its position is crucial for many cellular events, including migration and differentiation. Nuclear anchorage and movement can be achieved through association of outer nuclear membrane (ONM) proteins with the three cytoskeletal systems. Two decades ago studies described C. elegans mutants with defects in such events, but only recently has it been shown that the strategies for nuclear positioning are indeed conserved in C. elegans, Drosophila, mammals and potentially all eukaryotes. The integral ONM proteins implicated in these processes thus far all contain a conserved Klarsicht/ANC-1/Syne homology (KASH) domain at their C-terminus that can associate with Sad1p/UNC-84 (SUN)-domain proteins of the inner nuclear membrane within the periplasmic space of the nuclear envelope (NE). The complex thus formed is responsible not only for association with cytoplasmic elements but also for the integrity of the NE itself.

Woglar A et al. (2014) Chromosoma "Chromosome movement in meiosis I prophase of Caenorhabditis elegans."

Woglar A, Jantsch V

[Chromosoma, 2014]

Rapid chromosome movement during prophase of the first meiotic division has been observed in many organisms. It is generally concomitant with formation of the "meiotic chromosome bouquet," a special chromosome configuration in which one or both chromosome ends attach to the nuclear envelope and become concentrated within a limited area. The precise function of the chromosomal bouquet is still not fully understood. Chromosome mobility is implicated in homologous chromosome pairing, synaptonemal complex formation, recombination, and resolution of chromosome entanglements. The basic mechanistic module through which forces are exerted on chromosomes is widely conserved; however, phenotypic differences have been reported among various model organisms once movement is abrogated. Movements are transmitted to the chromosome ends by the nuclear membrane-bridging SUN/KASH complex and are dependent on cytoskeletal filaments and motor proteins located in the cytoplasm. Here we review the recent findings on chromosome mobility during meiosis in an animal model system: the Caenorhabditis elegans nematode.

Bone CR et al. (2016) J Cell Sci "Nuclear migration events throughout development."

Bone CR, Starr DA

[J Cell Sci, 2016]

Moving the nucleus to a specific position within the cell is an important event during many cell and developmental processes. Several different molecular mechanisms exist to position nuclei in various cell types. In this Commentary, we review the recent progress made in elucidating mechanisms of nuclear migration in a variety of important developmental models. Genetic approaches to identify mutations that disrupt nuclear migration in yeast, filamentous fungi, Caenorhabditis elegans, Drosophila melanogaster and plants led to the identification of microtubule motors, as well as Sad1p, UNC-84 (SUN) domain and Klarsicht, ANC-1, Syne homology (KASH) domain proteins (LINC complex) that function to connect nuclei to the cytoskeleton. We focus on how these proteins and various mechanisms move nuclei during vertebrate development, including processes related to wound healing of fibroblasts, fertilization, developing myotubes and the developing central nervous system. We also describe how nuclear migration is involved in cells that migrate through constricted spaces. On the basis of these findings, it is becoming increasingly clear that defects in nuclear positioning are associated with human diseases, syndromes and disorders.