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2017 ; 18
(1
): 180
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Topological organization and dynamic regulation of human tRNA genes during
macrophage differentiation
#MMPMID28931413
Van Bortle K
; Phanstiel DH
; Snyder MP
Genome Biol
2017[Sep]; 18
(1
): 180
PMID28931413
show ga
BACKGROUND: The human genome is hierarchically organized into local and
long-range structures that help shape cell-type-specific transcription patterns.
Transfer RNA (tRNA) genes (tDNAs), which are transcribed by RNA polymerase III
(RNAPIII) and encode RNA molecules responsible for translation, are dispersed
throughout the genome and, in many cases, linearly organized into genomic
clusters with other tDNAs. Whether the location and three-dimensional
organization of tDNAs contribute to the activity of these genes has remained
difficult to address, due in part to unique challenges related to tRNA
sequencing. We therefore devised integrated tDNA expression profiling, a method
that combines RNAPIII mapping with biotin-capture of nascent tRNAs. We apply this
method to the study of dynamic tRNA gene regulation during macrophage development
and further integrate these data with high-resolution maps of 3D chromatin
structure. RESULTS: Integrated tDNA expression profiling reveals domain-level and
loop-based organization of tRNA gene transcription during cellular
differentiation. tRNA genes connected by DNA loops, which are proximal to CTCF
binding sites and expressed at elevated levels compared to non-loop tDNAs, change
coordinately with tDNAs and protein-coding genes at distal ends of interactions
mapped by in situ Hi-C. We find that downregulated tRNA genes are specifically
marked by enhanced promoter-proximal binding of MAF1, a transcriptional repressor
of RNAPIII activity, altogether revealing multiple levels of tDNA regulation
during cellular differentiation. CONCLUSIONS: We present evidence of both local
and coordinated long-range regulation of human tDNA expression, suggesting the
location and organization of tRNA genes contribute to dynamic tDNA activity
during macrophage development.