Transcription-dependent spatial arrangements of CFTR and adjacent genes in human cell nuclei

The olfactory system translates a vast array of volatile chemicals into diverse odor perceptions and innate behaviors. Odor detection in the mouse nose is mediated by 1,000 different odorant receptors (ORs) and 14 trace amine-associated receptors (TAARs). ORs are used in a combinatorial manner to encode the unique identities of myriad odorants. However, some TAARs appear to be linked to innate responses, raising questions about regulatory mechanisms that might segregate OR and TAAR expression in appropriate subsets of olfactory sensory neurons (OSNs). Here, we report that OSNs that express TAARs comprise at least two subsets that are biased to express TAARs rather than ORs. The two subsets are further biased in Taar gene choice and their distribution within the sensory epithelium, with each subset preferentially expressing a subgroup of Taar genes within a particular spatial domain in the epithelium. Our studies reveal one mechanism that may regulate the segregation of Olfr (OR) and Taar expression in different OSNs: the sequestration of Olfr and Taar genes in different nuclear compartments. Although most Olfr genes colocalize near large central heterochromatin aggregates in the OSN nucleus, Taar genes are located primarily at the nuclear periphery, coincident with a thin rim of heterochromatin. Taar-expressing OSNs show a shift of one Taar allele away from the nuclear periphery. Furthermore, examination of hemizygous mice with a single Taar allele suggests that the activation of a Taar gene is accompanied by an escape from the peripheral repressive heterochromatin environment to a more permissive interior chromatin environment. olfactory receptor genes | Taar genes | nuclear organization

Section: Resultssupporting

confidence: 71%

Olfactory receptor genes expressed in distinct lineages are sequestered in different nuclear compartments

Yoon

Ragoczy

et al. 2015

“…Although the architectural organization of the nucleus is still poorly understood (6,7), repartitioning of active genes from interior to the periphery of nuclear territories has been suggested for Hox genes in ES cells (8), IgH in ␤ lymphocytes (9), c-maf in T cells (10), Mash1 in neuronal cells (11), and Cftr in adenocarcinoma cells (12). Many recent studies have documented interchromosomal interactions to provide novel control mechanisms for regulated gene expression in interphase nuclei (13)(14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Enhancing nuclear receptor-induced transcription requires nuclear motor and LSD1-dependent gene networking in interchromatin granules

Kwon

Núñez

et al. 2008

251

253

Fig. 2. Rapid induction of interchromosomal interactions by nuclear hormone signaling. (A) 3D-FISH confirmation of E 2 -induced (60 min) TFF1:GREB1 interchromosomal interactions in HMECs with the distribution of loci distances measured (box plot with scatter plot) and quantification of colocalization (bar graph) before and after E 2 treatment. Cells exhibiting mono-or biallelic interactions were combined for comparison with cells showing no colocalization; statistical significance in the bar graph was determined by χ 2 test (**, P < 0.001). (B) 2D FISH confirmation of the interchromosomal interactions in HMEC cells by combining chromosome paint (aqua) and specific DNA probes (green and red). (Upper) Illustrates two examples of mock-treated cells. (Lower) Shows the biallelic interactions/ nuclear reorganization after E 2 treatment for 60 min, exhibiting kissing events between chromosome 21 and chromosome 2. (C) Similar analysis on HMECs, but in this case using 3D FISH to paint chromosome 2 (red) and chromosome 21 (green), showing E 2 -induced chromosome 2-chromosome 21 interaction. Both assays revealed neither chromosome 21-chromosome 21 nor chromosome 2-chromosome 2 interactions in response to E 2. (D) Temporal kinetics of GREB1:TFF1 interactions by 3D FISH in HMECs (**, P < 0.001 by χ 2 ). (E-G) Nuclear microinjection of siRNA against ERα, CBP/p300, or SRC1/pCIP prevented E 2 -induced interchromosomal interactions, counting both mono-and biallelic interactions (**, P < 0.001 by χ 2 ). The injection of siER and siDLC1 were done in the same experiment, sharing the same control group. (H) Nuclear microinjection of siRNA against LSD1, which was shown to be required for estrogen-induced gene expression (22), did not block E 2 -induced interchromosomal interactions. The injection of siLSD1 and SRC1/pCIP were done in a single experiment, sharing the same control group.

“…In support of this suggestion, alterations in chromatin structure across large multigenic domains have been correlated to changes in gene expression (9)(10)(11)(12)(13). Repressed multigenic regions are frequently localized to nuclear periphery (14), and a number of studies linked derepression/ activation of genetic loci with their translocation away from the nuclear envelope (15)(16)(17)(18)(19)(20)(21). These observations suggest that tethering of genetic loci to nuclear lamina causes their silencing.…”

mentioning

confidence: 57%

The B-type lamin is required for somatic repression of testis-specific gene clusters

Shevelyov

Lavrov

Mikhaylova

et al. 2009

121

118

Large clusters of coexpressed tissue-specific genes are abundant on chromosomes of diverse species. The genes coordinately misexpressed in diverse diseases are also found in similar clusters, suggesting that evolutionarily conserved mechanisms regulate expression of large multigenic regions both in normal development and in its pathological disruptions. Studies on individual loci suggest that silent clusters of coregulated genes are embedded in repressed chromatin domains, often localized to the nuclear periphery. To test this model at the genome-wide scale, we studied transcriptional regulation of large testis-specific gene clusters in somatic tissues of Drosophila. These gene clusters showed a drastic paucity of known expressed transgene insertions, indicating that they indeed are embedded in repressed chromatin. Bioinformatics analysis suggested the major role for the B-type lamin, LamDmo, in repression of large testis-specific gene clusters, showing that in somatic cells as many as three-quarters of these clusters interact with LamDmo. Ablation of LamDmo by using mutants and RNAi led to detachment of testis-specific clusters from nuclear envelope and to their selective transcriptional up-regulation in somatic cells, thus providing the first direct evidence for involvement of the B-type lamin in tissue-specific gene repression. Finally, we found that transcriptional activation of the lamina-bound testis-specific gene cluster in male germ line is coupled with its translocation away from the nuclear envelope. Our studies, which directly link nuclear architecture with coordinated regulation of tissue-specific genes, advance understanding of the mechanisms underlying both normal cell differentiation and developmental disorders caused by lesions in the B-type lamins and interacting proteins.coexpressed genes ͉ nuclear lamina P revious studies by others and us have shown that many coexpressed tissue-specific genes are organized in large continuous clusters on chromosomes of diverse species (1-3), and similar clustering has been observed for the genes deregulated in diverse diseases (4-8). These findings imply that higherorder chromatin structure may be involved in regulation of extensive multigenic regions in both normal development and its pathological disruptions. In support of this suggestion, alterations in chromatin structure across large multigenic domains have been correlated to changes in gene expression (9-13). Repressed multigenic regions are frequently localized to nuclear periphery (14), and a number of studies linked derepression/ activation of genetic loci with their translocation away from the nuclear envelope (15-21). These observations suggest that tethering of genetic loci to nuclear lamina causes their silencing. Recent reports of repression of integrated transgenes and adjacent endogenous genes upon their artificial recruitment to the nuclear envelope (21, 22) support this hypothesis; however, similar studies on different loci did not show repression (23,24) indicating that silencing at nuclear ...