PMID- 34339482
OWN - NLM
STAT- MEDLINE
DCOM- 20211130
LR  - 20211130
IS  - 1553-7374 (Electronic)
IS  - 1553-7366 (Print)
IS  - 1553-7366 (Linking)
VI  - 17
IP  - 8
DP  - 2021 Aug
TI  - Cytomegalovirus late transcription factor target sequence diversity orchestrates 
      viral early to late transcription.
PG  - e1009796
LID - 10.1371/journal.ppat.1009796 [doi]
LID - e1009796
AB  - Beta- and gammaherpesviruses late transcription factors (LTFs) target viral 
      promoters containing a TATT sequence to drive transcription after viral DNA 
      replication has begun. Human cytomegalovirus (HCMV), a betaherpesvirus, uses the 
      UL87 LTF to bind both TATT and host RNA polymerase II (Pol II), whereas the UL79 
      LTF has been suggested to drive productive elongation. Here we apply integrated 
      functional genomics (dTag system, PRO-Seq, ChIP-Seq, and promoter function 
      assays) to uncover the contribution of diversity in LTF target sequences in 
      determining degree and scope to which LTFs drive viral transcription. We 
      characterize the DNA sequence patterns in LTF-responsive and -unresponsive 
      promoter populations, determine where and when Pol II initiates transcription, 
      identify sites of LTF binding genome-wide, and quantify change in nascent 
      transcripts from individual promoters in relation to core promoter sequences, LTF 
      loss, stage of infection, and viral DNA replication. We find that HCMV UL79 and 
      UL87 LTFs function concordantly to initiate transcription from over half of all 
      active viral promoters in late infection, while not appreciably affecting host 
      transcription. Both LTFs act on and bind to viral early-late and late 
      kinetic-class promoters. Over one-third of these core promoters lack the TATT and 
      instead have a TATAT, TGTT, or YRYT. The TATT and non-TATT motifs are part of a 
      sequence block with a sequence code that correlates with promoter transcription 
      level. LTF occupancy of a TATATA palindrome shared by back-to-back promoters is 
      linked to bidirectional transcription. We conclude that diversity in LTF target 
      sequences shapes the LTF-transformative program that drives the viral 
      early-to-late transcription switch.
FAU - Li, Ming
AU  - Li M
AUID- ORCID: 0000-0003-0396-4078
AD  - Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, United States of 
      America.
AD  - Department of Internal Medicine University of Iowa, Iowa City, Iowa, United 
      States of America.
FAU - Hu, Qiaolin
AU  - Hu Q
AUID- ORCID: 0000-0001-6236-0261
AD  - Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, United States of 
      America.
AD  - Department of Internal Medicine University of Iowa, Iowa City, Iowa, United 
      States of America.
FAU - Collins, Geoffrey
AU  - Collins G
AD  - Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of 
      America.
FAU - Parida, Mrutyunjaya
AU  - Parida M
AUID- ORCID: 0000-0002-2146-5101
AD  - Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of 
      America.
FAU - Ball, Christopher B
AU  - Ball CB
AUID- ORCID: 0000-0002-5983-1605
AD  - Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of 
      America.
FAU - Price, David H
AU  - Price DH
AD  - Department of Biochemistry, University of Iowa, Iowa City, Iowa, United States of 
      America.
FAU - Meier, Jeffery L
AU  - Meier JL
AUID- ORCID: 0000-0001-9491-1697
AD  - Iowa City Veterans Affairs Health Care System, Iowa City, Iowa, United States of 
      America.
AD  - Department of Internal Medicine University of Iowa, Iowa City, Iowa, United 
      States of America.
AD  - Department of Epidemiology, University of Iowa, Iowa City, Iowa, United States of 
      America.
LA  - eng
GR  - I01 BX004434/BX/BLRD VA/United States
GR  - R21 AI130453/AI/NIAID NIH HHS/United States
GR  - R35 GM126908/GM/NIGMS NIH HHS/United States
GR  - T32 AI007533/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210802
PL  - United States
TA  - PLoS Pathog
JT  - PLoS pathogens
JID - 101238921
RN  - 0 (DNA, Viral)
RN  - 0 (Transcription Factors)
RN  - 0 (Viral Proteins)
RN  - EC 2.7.7.- (RNA Polymerase II)
SB  - IM
MH  - Cytomegalovirus/*physiology
MH  - Cytomegalovirus Infections/genetics/*virology
MH  - *DNA Replication
MH  - DNA, Viral/genetics/metabolism
MH  - Gene Expression Regulation, Viral
MH  - Humans
MH  - Promoter Regions, Genetic
MH  - RNA Polymerase II/genetics/*metabolism
MH  - Transcription Factors/genetics/*metabolism
MH  - Transcription, Genetic
MH  - Viral Proteins/genetics/*metabolism
MH  - *Virus Replication
PMC - PMC8360532
COIS- The authors have declared that no competing interests exist.
EDAT- 2021/08/03 06:00
MHDA- 2021/12/01 06:00
PMCR- 2021/08/02
CRDT- 2021/08/02 17:19
PHST- 2021/03/16 00:00 [received]
PHST- 2021/07/12 00:00 [accepted]
PHST- 2021/08/12 00:00 [revised]
PHST- 2021/08/03 06:00 [pubmed]
PHST- 2021/12/01 06:00 [medline]
PHST- 2021/08/02 17:19 [entrez]
PHST- 2021/08/02 00:00 [pmc-release]
AID - PPATHOGENS-D-21-00577 [pii]
AID - 10.1371/journal.ppat.1009796 [doi]
PST - epublish
SO  - PLoS Pathog. 2021 Aug 2;17(8):e1009796. doi: 10.1371/journal.ppat.1009796. 
      eCollection 2021 Aug.