Science

Research interests

Trained as a molecular and cell biologist, Juntao is broadly interested in the transmission and maintenance of biological information. His current research aims to uncover the genetic and epigenetic mechanisms that underlie the heritability of traits.

Juntao is a question-driven scientist. His research is guided by fundamental questions such as:

Epigenetics: How are different forms of epigenetic information—including histone modifications, small RNAs/lncRNAs, DNA methylation, and transcription factor networks—transmitted during cell division?
Stem cell: How do developmental cues work with chromatin to specify and maintain cell identity?
DNA replication: How is DNA replication coupled with the duplication of chromosomes?
Chromatin dynamics: How is chromatin structure maintained during essential DNA-associated metabolisms, such as replication, repair, and recombination?
Gene regulation: How do distal regulatory elements, such as enhancers, evolve and communicate with target genes to achieve specificity in transcriptional activation?
Systems biology: What are the molecular basis and general principles of stable biological memory, such as the memory that governs cell identities, or the memory encoded in neural circuits?

To address these questions, Juntao integrates genetic, genomic, biochemical, biophysical, and structural approaches, with the goal of understanding general principles of biological memory and its inheritance.

Ph.D. thesis: How are parental histones inherited during DNA replication?

Main question

Numerous studies over the past forty years have demonstrated the random distribution of parental histones to the two daughter strands during DNA replication. The inheritance of parental histones is thought to play an important role in serving as templates for "read-write" mechanism carried out by histone-modifying enzymes to restore epigenetic information. Recent advancements have identified several replisome histone-binding proteins required for symmetrical histone inheritance. However, the mechanism by which the intact parental H3-H4 tetramers are transferred from the front of the replication fork to the back remains unclear. Juntao's Ph.D. thesis in the Moazed Lab aims to uncover the mechanism underlying parental histone inheritance and understand its contribution to epigenetic inheritance using the fission yeast Schizosacchryomyces pombe as a model system.

Mrc1/CLASPIN contains an evolutionary conserved H3-H4 tetramer binding domain

Combining in vivo S. pombe heterochromatin maintenance system and structural predictions with AlphaFold-Multimer, he discovered that the non-essential replication checkpoint factor Mrc1/CLASPIN contains an evolutionarily conserved H3-H4 tetramer binding activity that is independent of its checkpoint function. Heterochromatin maintenance requires this histone binding activity but not checkpoint domain in both the budding yeast Saccharomyces cerevisiae and the fission yeast S. pombe, suggesting the function of Mrc1 in parental histone inheritance is conserved during evolution. The predicted Mrc1 histone binding domain is structurally and physically similar to the complex formed when nucleosomal DNA, H2B, and H2A bind to the H3-H4 tetramer, suggesting that Mrc1/CLASPIN has evolved nucleosome-like properties to protect H3-H4 tetramers during DNA replication for inheritance. The AlphaFold prediction was further validated with in vitro biochemical reconstitution, biophysical measurement of complex formation, and in vivo genetics demonstrating the requirement of Mrc1 histone binding activity in maintaining gene silencing in both S. cerevisiae and S. pombe.

Mrc1 distributes parental histones to both daughter DNA strands

Through collaborations with Li Lab (Peking University) as well as Jia Lab and Zhang Lab (Columbia University), they discovered mutations in the Mrc1 histone binding domain (HBD) showed no apparent strand bias, but resulted in reduced parental histone density at both the leading and lagging strand, suggesting Mrc1 contributes to parental histone transfer to both daughter DNA strands. AlphaFold-Multimer prediction further suggested Mrc1 HBD localizes at the center of the replication fork via an interaction interface formed by Cdc45 and Mcm2. Together, these data suggested a model that Mrc1 is a parental histone transfer distribution site in the replisome (Yu, Zhang et al., PMID: 39094570, 2024).

Replisome contains parental histone inheritance intermediate sites

Additional AlphaFold predictions suggest other replisome histone binding proteins also interact with various replisome components. Therefore, they propose parental histones are inherited through multiple intermediate sites in the replisome (Yu, Zhang et al., PMID: 39094570, 2024), including:

P site, when parental histones are captured by FACT complex at the parental nucleosome encountering the replisome.
D-Swi1 site, when Swi1 recruits FACT-histone complex to the replisome for distributing parental histones.
D-Mrc1 site, formed by Mrc1-Cdc45/Mcm2 to distribute parental histones to both daughter DNA strands.
LG1 site, formed by Mcm2-FACT-Swi1 to facilitate parental histone inheritance to the lagging strand.
LG2 site, formed by Pol1-FACT-Mcl1 to facilitate parental histone inheritance to the lagging strand.
LD1 site, formed by Dpb3-Dpb4 to facilitate parental histone inheritance to the leading strand.

Future experiments are required to validate all AlphaFold predictions and determine the dynamics of histone inheritance between these intermediate sites.

Undergraduate research: How do enhancers find their target genes to activate transcription?

Before graduate school, he did his undergraduate study at the University of Science and Technology of China (USTC) and received a B.S. in Biology with honorary rank in 2017. During his senior undergraduate year, he worked with Dr. Bing Ren at the University of California San Diego and contributed to a study led by Dr. Yarui Diao to map the enhancer landscape of POU5F1/OCT4 in human embryonic stem cells using genome editing coupled with high-throughput sequencing (CREST-Seq, Diao, Fang, Li et al., PMID: 28417999, 2017). His undergraduate thesis was recognized as an outstanding undergraduate thesis of the Class of 2017, USTC.

Juntao is continuously interested in how genes are selectively activated. In particular, he is interested in how enhancers are activated during development, how enhancers find their target genes, and the role of genome organization in the specificity of enhancer-promoter contact.

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