Structure and function of the nucleus: anatomy and physiology of chromatin

Abstract

A review of the literature accumulated recently on nuclear structure and function reveals that: (1) The nucleus is the interphase form of chromosomes (chromatin organizes and compartmentalizes the nucleus). (2) These organizational programs are morphogenetic in nature and are regulated by both DNA content and by epigenetic interactions. (3) In mammals with a diploid complement, it is very likely that chromosomes construct interphase domains based on their structural milieu (including any imprinted areas). These are the same structured areas that correspond to G- and R-bands with their varying DNA content and early versus late replication. (4) Changes in a position of a segment of DNA from one chromatin environment to another changes its availability to early replication factors and transcription factors as well as its nuclear positioning and chromatin architecture. This process was first described as positional effect variegation in Drosophila but is now found to be more general and explains many cases of direct clinical relevance. Examples in mammals include spreading of X inactivation, imprinting and changes in chromatin associated with chromosome translocation. (5) Chromosomal autoconstruction and reconstruction into a functional nucleus are altered during cell cycle and during differentiation (much more work needed on this area).

A translocation causing increased α-Klotho level results in hypophosphatemic rickets and hyperparathyroidism

“…The elevated FGF23 and PTH levels in this patient provide evidence of ␣-Klotho's effects on these pathways in vivo. We infer that the increased ␣-Klotho levels seen in this patient are due to a positional effect of the translocation, a mechanism well established in model systems such as Drosophila melanogaster (28,29) and that plays a role in several human disease states such as Rieger syndrome (30) and holoprosencephaly (31). Importantly, mice with hypophosphatemia due to mutation in PHEX, have low Klotho levels, excluding the possibility that the observed high levels of Klotho in our patient are simply a secondary consequence of hypophosphatemia (32).…”

TheDrosophilaNuclear Lamina Protein YA Binds to DNA and Histone H2B with Four Domains

“…Chromosome condensation state is important for nuclear functions such as DNA replication, transcription, and chromosome segregation (for reviews, see Koshland and Strunnikov, 1996;Wolffe, 1996;Qumsiyeh, 1999) and is an active process that requires chromosome decondensation and condensation factors. The YA phenotype (Liu et al, 1995;Berman, 2000) suggests that YA may be essential to attain the proper chromatin condensation state at the end of female meiosis in Drosophila and is most consistent with YA's action being to decondense the chromatin following meiosis.…”

Effect of Robertsonian Translocations on the Motor Activity Rhythm in the House Mouse

“…Spatial changes in chromatin structure, either in metaphase or in interphase, are related to replication and transcription, thereby affecting cell function (Qumsiyeh, 1999), and thus influencing the ultradian rhythm of cell metabolism. Ultradian rhythms are present in physiological processes such as carbon dioxide emission (Stupfel et al, 1995), oxygen consumption (Bailey et al, 1973), internal temperature (Roussel, 1986), hormone secretions (Bradenberger et al, 1987), etc.…”

“…Gene expression depends on chromosomal organization within interphase nucleus (Heslop-Harrison and Benet, 1990;Park and De Boni, 1998;Qumsiyeh, 1999) and changes in this chromosomal spatial pattern produced by structural rearrangements, such as Robertsonian fusions, may induce alterations in the genome function (Qumsiyeh, 1999;White, 1975). Since most of the genes encoding the mammalian circadian clock are located in the chromosomes involved in the Robertsonian fusions of the Barcelona polymorphic area, variations in the spatial position of these genes, and others that contribute to multiple aspects of circadian behavior (Shimomura et al, 2001), could modify characteristics of the biological clock.…”