Nucleosomes in gene regulation: theoretical approaches

This work reviews current theoretical approaches of biophysics and bioinformatics for the description of nucleosome arrangements in chromatin and transcription factor binding to nucleosomal organized DNA. The role of nucleosomes in gene regulation is discussed from molecular-mechanistic and biological point of view. In addition to classical problems of this field, actual questions of epigenetic regulation are discussed. The authors selected for discussion what seem to be the most interesting concepts and hypotheses. Mathematical approaches are described in a simplified language to attract attention to the most important directions of this field

The LINC-less granulocyte nucleus

The major blood granulocyte (neutrophil) is rapidly recruited to sites of bacterial and fungal infections. It is a highly malleable cell, allowing it to squeeze out of blood vessels and migrate through tight tissue spaces. The human granulocyte nucleus is lobulated and exhibits a paucity of nuclear lamins, increasing its capability for deformation. The present study examined the existence of protein connections between the nuclear envelope and cytoskeletal elements (the LINC complex) in differentiated cell states (i.e. granulocytic, monocytic and macrophage) of the human leukemic cell line HL-60, as well as in human blood leukocytes. HL-60 granulocytes exhibited a deficiency of several LINC complex proteins (i.e. nesprin 1 giant, nesprin 2 giant, SUN1, plectin and vimentin); whereas, the macrophage state revealed nesprin 1 giant, plectin and vimentin. Both states possessed SUN2 in the nuclear envelope. Parallel differences were observed with some of the LINC complex proteins in isolated human blood leukocytes, including macrophage cells derived from blood monocytes. The present study documenting the paucity of LINC complex proteins in granulocytic forms, in combination with previous data on granulocyte nuclear shape and nuclear envelope composition, suggest the hypothesis that these adaptations evolved to facilitate granulocyte cellular malleability

Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly

The nature of the wild-type gene product at the mouse ichthyosis (ic) locus has been of great interest because mutations at this locus cause marked abnormalities in nuclear heterochromatin, similar to those observed in Pelger-Huët anomaly (PHA). We recently found that human PHA is caused by mutations in the gene (LBR) encoding lamin B receptor, an evolutionarily conserved inner nuclear membrane protein involved in nuclear assembly and chromatin binding. Mice homozygous for deleterious alleles at the ichthyosis (ic) locus present with a blood phenotype similar to PHA, and develop other phenotypic abnormalities, including alopecia, variable expression of syndactyly and hydrocephalus. The ic locus on mouse chromosome 1 shares conserved synteny with the chromosomal location of the human LBR locus on human chromosome 1. In this study, we identified one nonsense (815ins) and two frameshift mutations (1088insCC and 1884insGGAA) within the Lbr gene of mice homozygous for either of three independent mutations (ic, ic(J) and ic(4J), respectively) at the ichthyosis locus. These allelic mutations are predicted to result in truncated or severely impaired LBR protein. Our studies of mice homozygous for the ic(J) mutation revealed a complete loss of LBR protein as shown by immunofluorescence microscopy and immunoblotting. The findings provide the molecular basis for the heterochromatin clumping and other distinct phenotypes caused by ic mutations. These spontaneous Lbr mutations confirm the molecular basis of human PHA and provide a small animal model for determination of the precise function of LBR in normal and pathological states