The mammalian cell nucleus displays a distinct spatial segregation of active euchromatic from inactive heterochromatic genomic regions 1,2. In conventional nuclei, microscopy shows that euchromatin is localized in the nuclear interior and heterochromatin at the nuclear periphery 1,2. Hi-C shows this segregation as a plaid pattern of enriched contacts between A (euchromatic) and B (heterochromatic) compartments 3. Many mechanisms of compartment formation have been proposed, such as attraction of heterochromatin to the nuclear lamina 2,4 , preferential attraction of similar chromatin to each other 1,4-12 , higher levels of chromatin mobility in the active chromatin 13-15 , and transcription-related clustering of euchromatin 16,17. Still, these hypotheses have remained inconclusive due to the difficulty of disentangling intra-chromatin and chromatin-#

Genome-wide molecular studies have provided new insights into the organization of nuclear chromatin by revealing the presence of chromatin domains of differing transcriptional activity, frequency of cis-interactions, proximity to scaffolding structures and replication timing. These studies have not only brought our understanding of genome function to a new level, but also offered functional insight for many phenomena observed in microscopic studies. In this review, we discuss the major principles of nuclear organization based on the spatial segregation of euchromatin and heterochromatin, as well as the dynamic genome rearrangements occurring during cell differentiation and development. We hope to unite the existing molecular and microscopic data on genome organization to get a holistic view of the nucleus, and propose a model, in which repeat repertoire together with scaffolding structures blueprint the functional nuclear architecture.

To improve light propagation through the retina, the rod nuclei of nocturnal mammals are uniquely changed compared to the nuclei of other cells. In particular, the main classes of chromatin are segregated in them and form regular concentric shells in order; inverted in comparison to conventional nuclei. A broad study of the epigenetic landscape of the inverted and conventional mouse retinal nuclei indicated several differences between them and several features of general interest for the organization of the mammalian nuclei. In difference to nuclei with conventional architecture, the packing density of pericentromeric satellites and LINE-rich chromatin is similar in inverted rod nuclei; euchromatin has a lower packing density in both cases. A high global chromatin condensation in rod nuclei minimizes the structural difference between active and inactive X chromosome homologues. DNA methylation is observed primarily in the chromocenter, Dnmt1 is primarily associated with the euchromatic shell. Heterochromatin proteins HP1-alpha and HP1-beta localize in heterochromatic shells, whereas HP1-gamma is associated with euchromatin. For most of the 25 studied histone modifications, we observed predominant colocalization with a certain main chromatin class. Both inversions in rod nuclei and maintenance of peripheral heterochromatin in conventional nuclei are not affected by a loss or depletion of the major silencing core histone modifications in respective knock-out mice, but for different reasons. Maintenance of peripheral heterochromatin appears to be ensured by redundancy both at the level of enzymes setting the epigenetic code (writers) and the code itself, whereas inversion in rods rely on the absence of the peripheral heterochromatin tethers (absence of code readers).

Transcription is the first step on the complex way of converting genetic information into proteins. In recent years, various studies have contributed to a vast knowledge about eukaryotic transcription -on both the global nuclear and the molecular level. However, knowledge pertaining to an intermediate level of transcriptional organization, that is how individual expressed genes are spatially organized, is surprisingly