Getting connected in the globin interactome

Abstract

n e w s a n d v i e w s candidate genes (AGER, TNS1, HTR4, THSD4 and GSTCD) were shown to be expressed in lung tissue 2 . These loci are all biologically plausible candidates that are involved in pathways known to be important in lung biology, including immune function, muscle function or inflammation. These studies did not replicate the SERPINE2 association and also did not find evidence for association to the 15q CHRNA5-CHRNA3-CHRNB4 locus previously associated with nicotine dependence, lung cancer and COPD [11][12][13] . Clinical relevanceLung function levels depend strongly on age, height and gender, with distinct changes from childhood to adulthood (Fig. 1). Thus, because of study-design considerations, some gene variants identified in the two studies reported here may simply influence lung function in nondiseased subjects and will have no independent effect on patients with airways disease. However, the high withinindividual consistency of spirometric lung function measures over time, and the links of the identified candidate genes to lung development, suggest that genetic variations associated with lung function development might be important genetic determinants of lung function in both healthy individuals and those with airways disease (asthma and COPD). To test this hypothesis, the newly associated variants should be tested in both individuals with asthma and those with COPD. These studies should also be extended to include bronchodilator and bronchoconstrictor responses.These loci account for a small proportion of the variation in FEV 1 and the FEV 1 /FVC ratio. Repapi et al. 2 estimates that the five new loci identified in their study account for ~0.14% of the variation in FEV 1 /FVC ratio. Translating this to clinical prediction remains further away, and the first steps toward this goal include additional validation, refinement of the genetic loci and determination of the specific genes and their functional variants, as well as more accurate estimation of effect sizes from additional studies of unaffected and diseased subjects. The organization of a eukaryotic nucleus reflects its specific expression profile 1,2 . On the genomic scale, this translates to preferred tissue-specific chromatin folding and chromosome positioning within interphase nuclei, including intermingling of looped segments within and between chromosomes 3,4 . Consequently, co-regulated genes tend to localize near each other at activity hubs. However, the description of colocalized and coexpressed genes has been anecdotal and limited to a few genes. What had been missing until recently 5,6 was information on how extensive and consistent these associations are at the genomic level. On page 53 of this issue, Peter Fraser and colleagues 7 use an array of biochemical and cytogenetic approaches to elegantly describe such a genomic transcription interactome by exploring the gene associations of the mouse α-(Hba) and β-globin (Hbb) loci in erythroid cells. Globins cast a wide netThe globin genes are highly expressed in developing eryth...

Innate Structure of DNA Foci Restricts the Mixing of DNA from Different Chromosome Territories

“…5) can be sufficient to allow the formation of widespread gene interactions while preserving CTs as higher-order chromatin structures. As a growing body of evidence supports the formation of cell type specific ‘interactomes’ during cell differentiation [18]–[23], it is important to understand how different patterns of gene expression correlate with the formation of interaction networks and how these interactions define spatial and temporal changes in genome structure and function within individual cells.…”

“…However, validation of specific inter-chromosomal interactions within individual cells typically demonstrated that only ∼10% of the loci in question were co-associated when transcribed [19], [21], [22]. Nevertheless, recent innovations in analysis of genome-wide interaction networks or functional ‘interactomes’, have placed unprecedented emphasis on understanding how chromatin dynamics facilitate the formation of gene interactions networks, which in turn might contribute to the regulation of gene expression in mammalian cells [18], [23].…”