Abstract
BackgroundIn homeotherms, the alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes. Terminal erythroid differentiation results in dramatic upregulation of alpha-globin genes making their expression comparable to the rRNA transcriptional output. Little is known about the influence of the erythroid-specific alpha-globin gene transcription outburst on adjacent, widely expressed genes and large-scale chromatin organization. Here, we have analyzed the total transcription output, the overall chromatin contact profile, and CTCF binding within the 2.7 Mb segment of chicken chromosome 14 harboring the alpha-globin gene cluster in cultured lymphoid cells and cultured erythroid cells before and after induction of terminal erythroid differentiation.ResultsWe found that, similarly to mammalian genome, the chicken genomes is organized in TADs and compartments. Full activation of the alpha-globin gene transcription in differentiated erythroid cells is correlated with upregulation of several adjacent housekeeping genes and the emergence of abundant intergenic transcription. An extended chromosome region encompassing the alpha-globin cluster becomes significantly decompacted in differentiated erythroid cells, and depleted in CTCF binding and CTCF-anchored chromatin loops, while the sub-TAD harboring alpha-globin gene cluster and the upstream major regulatory element (MRE) becomes highly enriched with chromatin interactions as compared to lymphoid and proliferating erythroid cells. The alpha-globin gene domain and the neighboring loci reside within the A-like chromatin compartment in both lymphoid and erythroid cells and become further segregated from the upstream gene desert upon terminal erythroid differentiation.ConclusionsOur findings demonstrate that the effects of tissue-specific transcription activation are not restricted to the host genomic locus but affect the overall chromatin structure and transcriptional output of the encompassing topologically associating domain.
Highlights
In homeotherms, the alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes
We have found that transcription outburst of the alphaglobin genes in terminally differentiated erythroblasts is accompanied by (i) a substantial increase in the level of transcription of several adjacent housekeeping genes and intergenic regions, (ii) dramatic compaction of the encompassing sub-topologically associating domain (TAD) amid the chromatin decompaction and massive attenuation of CTCF binding within the extended chromosome vicinity, and (iii) large-scale changes in the chromatin interaction profile at the level of chromatin compartments including segregation of alpha-globin gene domain (AgGD) from the transcriptionally silent gene desert
The differential expression analysis reveals the upregulation of numerous erythroid genes in differentiated HD3 cells (Fig. 1a), including genes encoding transcription factors (KLF1, GATA2, SCL, LMO2, NF-E2 and FOG1), enzymes involved in heme synthesis and cell surface markers
Summary
The alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes. The AgGD is located in a permanently open (DNAse I-sensitive) highly acetylated chromatin in all cell types [15], full activation of the alpha-globin transcription in differentiated erythroid cells is accompanied by further histone hyperacetylation [16, 17] and reconfiguration of the local chromatin spatial structure within the domain. In these cells, MRE interacts with the adult alpha-globin gene promoters via direct looping, and this interaction is a prerequisite for proper development stage-specific expression of the adult alpha-globin genes [18, 19]
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