Yang Lab · School of Life Sciences and Technology · Tongji University, Shanghai
Our lab uncovered how KRAB zinc-finger proteins recognise and silence ancient viral DNA in mammalian genomes. We are now building on that work with computational enzyme design and electrochemical sensors for continuous glucose (CGM) and ketone (CKM) monitoring.
Shown: our crystal structure of the eleven-finger ZFP568 array gripping its DNA target (PDB 5V3M, Cell 2018). Drag to rotate.
Research at a glance
How the largest family of human transcription factors finds and silences endogenous retroviruses, and how it controls embryonic and placental growth.
Our published work 02Using generative AI and structure prediction to design enzymes that are more stable, more active and better suited to sensors, then testing them in the lab.
New direction 03Enzyme-electrode sensors that continuously track glucose and β-hydroxybutyrate in interstitial fluid, giving early warning of diabetic ketoacidosis.
New directionFilms
Each runs two to three minutes and is narrated in English.
How zinc-finger proteins tame ancient retroviruses in our DNA, as shown in our papers in Science, Cell, PNAS and NAR.
From reading how natural proteins recognise DNA to designing enzymes with generative models.
How an enzyme electrode under the skin turns glucose and ketones into a continuous electrical signal.
Selected findings
ZFP568 directly silences a placenta-specific Igf2 transcript. Deleting Igf2 rescues the gastrulation failure of Zfp568-null embryos.
Crystal structures of the eleven-finger ZFP568 array show fingers contacting 2–4 bases each. This breaks the textbook “one finger, three bases” rule.
Mouse ZFP961 and human ZNF417/ZNF587 recognise the PBS-Lys sequence. They repress retroviral integration and transcription, and losing them makes cells more susceptible to HIV-1 infection.
ZNF506 binds the proline primer-binding site and silences ERVs that use it. It evolved independently of the mouse protein ZFP809, which does the same job.
Principal Investigator
Tenured Professor, School of Life Sciences and Technology, Tongji University
Peng Yang trained at Nanjing University and Peking University, with postdoctoral work at HHMI and the U.S. National Institutes of Health. He started his lab at Tongji University in 2018. His first-author and co-first-author papers in Science and Cell showed how KRAB zinc-finger proteins regulate fetal and placental growth and how they recognise DNA. As corresponding author, his lab has since published on retroviral defense in PNAS, Nucleic Acids Research, Cell Research and Science Bulletin.
Work with us
We welcome collaboration with companies working on continuous glucose and ketone monitoring, biosensor enzymes and enzyme engineering. We are open to sponsored research, joint development and technology licensing.
Join us
We are looking for postdoctoral fellows, graduate students and undergraduate interns who want to work where molecular biology, computation and engineering meet.
Research
For a decade we have studied how zinc-finger proteins recognise DNA and defend the genome. We are now using that understanding to design enzymes and to build electrochemical sensors that monitor metabolism continuously.
About 8% of the human genome is made of ancient retroviruses that once infected the germ line of our ancestors. These endogenous retroviruses (ERVs) still carry promoters, enhancers and the tRNA primer-binding sites (PBS) that viruses use to start reverse transcription. If they are not kept in check, they can disrupt genes and destabilise the genome.
Mammals control them with KRAB zinc-finger proteins (KZFPs). With about 350 members, this is the largest family of transcription factors in the human genome. Each KZFP reads a specific DNA sequence with a tandem array of zinc fingers. Its KRAB domain then recruits KAP1 and the H3K9 methyltransferase SETDB1, which pack the target into silent heterochromatin.
We have identified which zinc-finger proteins recognise which viral elements and solved how long finger arrays read DNA. We have also shown that the same machinery was co-opted to control embryonic and placental growth.
A short film about our published work, narrated in English.
A KZFP represses the placenta-specific Igf2-P0 transcript. Deleting Igf2 rescues Zfp568-null gastrulation defects.
Cell 2018In crystal structures, single fingers contact 2–4 bases and an AT-rich stretch reshapes the DNA, so the array adapts to its target.
PNAS 2022ZFP961 in mouse and ZNF417/ZNF587 in human recognise PBS-Lys, the site HIV-1 uses, and restrict retroviral integration and transcription.
NAR 2023A human KZFP evolved independently of mouse ZFP809 to silence ERVs that use the proline primer.
Our structures of ZFP568 showed how precisely, and how flexibly, a protein can recognise its target. Enzymes add one more demand. They must hold a substrate and a cofactor in exactly the right geometry to make chemistry happen, and keep doing so under harsh conditions.
We use generative AI and structure prediction to redesign existing enzymes and create new ones. We start from the reaction: the substrate, the cofactor and the catalytic geometry. Diffusion models build backbones around that active site, inverse-folding networks write the sequences, and structure prediction filters the designs before we test them. In-house GPU computing sits next to our expression and enzyme-assay pipeline, so every round of designs is tested quickly and the results feed back into the next.
A short film about our enzyme design program, narrated in English.
Define the reaction: substrate, cofactor and catalytic geometry.
Diffusion models build protein backbones around the active site.
Inverse-folding networks design sequences that hold the catalytic residues in place.
Structure prediction checks the fold and the active-site geometry.
Express and purify the designs, then measure activity and stability. The results feed the next round.
This program is new. We will post results here as they are published.
More than half a billion adults worldwide live with diabetes. Continuous glucose monitors (CGMs) have transformed their care: a thin, enzyme-coated filament under the skin reads glucose in interstitial fluid every few minutes.
Glucose is only half the picture, though. A rise in the ketone β-hydroxybutyrate (BHB) is the earliest warning of diabetic ketoacidosis, a life-threatening emergency. The risk is especially high after insulin-pump failure and during SGLT2-inhibitor therapy. Continuous ketone monitoring (CKM) aims to catch that rise as it happens, instead of at the next finger-prick test.
Both sensors are electrochemical. An enzyme oxidises its target, and the released electrons are carried to an electrode, so the current is proportional to concentration.
Ketone sensing has a specific weakness. β-Hydroxybutyrate dehydrogenase cannot work without its cofactor NAD⁺, and in today's CKM sensors NAD⁺ gradually leaches out of the sensing layer. As the cofactor is lost, sensitivity falls and the signal drifts over the days of wear.
A short film about our CGM and CKM program, narrated in English.
Sensors must work for 14 days or more at 37 °C. Our enzyme design work aims to make the enzymes survive that long.
Redox mediators, enzyme-wiring hydrogels or direct electron transfer remove the dependence on oxygen and keep the signal stable.
Outer membranes and low operating potentials keep ascorbate, urate and acetaminophen from distorting the reading.
One filament that reads both analytes, so a dangerous combination is flagged as soon as it appears.
This program is new. We will post results here as they are published.
Publications
Peer-reviewed work by Peng Yang. Each entry gives a short summary and his role on the paper; full author lists are on the publisher's page. For an up-to-date record, see ORCID or Google Scholar.
Presents ZRdb, our database of human KZFPs and repeats (LTR, SINE, LINE and SVA elements). It combines KZFP sequences, domains and DNA-binding motifs with published ChIP-seq data, then maps and ranks by reliability which KZFPs bind and repress which retrotransposons and how the two families co-evolved.
Identifies ZNF506 as the human KZFP that binds the proline tRNA primer-binding site (PBS-Pro) and silences retroviruses that use it. ZNF506 evolved independently of the mouse protein ZFP809, which does the same job. The study also explores a link between ZNF506 and leukemia.
Combines a survey of PBS loci within ERVs with KZFP ChIP-seq to find zinc-finger proteins that target specific primer-binding sites. Mouse ZFP961 and human ZNF417/ZNF587 bind PBS-Lys, the site used by HIV-1. They repress retroviral integration and transcription, and losing them makes cells more susceptible to HIV-1.
Identifies ALPPL2 as a surface marker specific to naive human pluripotency. ALPPL2 is needed to establish and maintain the naive state, and works by stabilising the mRNAs of key naive transcription factors.
Shows that in mouse embryos the transcription factor Dux enhances zygotic genome activation at the 2-cell stage rather than starting it. Dux must also be degraded promptly, because prolonged expression stalls development.
From doctoral training at Peking University and research at NIBS (Beijing), HHMI and the U.S. National Institutes of Health.
Crystal structures of the eleven-finger ZFP568 array bound to its 24-bp target in the Igf2 promoter. Single fingers contact 2–4 bases and read thymine on the opposite strand, and an AT-rich stretch narrows the minor groove. Zinc-finger arrays therefore adapt to DNA shape instead of following a strict one-finger, three-base code.
ZFP568, a member of the KRAB zinc-finger family best known for silencing retroelements, directly represses a placenta-specific Igf2 transcript (Igf2-P0). Deleting Igf2 rescues the gastrulation failure of Zfp568-null embryos, which reveals a new layer of control over the main fetal growth hormone.
A review of how KRAB-ZFPs recognise and silence transposable elements, the arms-race model of their evolution, and how some were domesticated for host innovations such as imprinting, recombination hotspots and placental growth.
Shows that the LSD1 co-repressor Rcor2 drives cortical neurogenesis by repressing Dlx2 and Shh in the developing neocortex.
ZFP809 starts sequence-specific silencing of endogenous retroviruses during embryonic development by recruiting heterochromatin-forming complexes. It becomes largely dispensable in somatic tissues.
An essay on how maternal histone variants and their chaperones reprogram the paternal genome after fertilisation, and how this knowledge could improve somatic cell reprogramming.
A gain-of-function Tnni2 mutation that causes distal arthrogryposis impairs bone development by raising Hif3a expression and lowering Vegf.
RCOR2 forms a complex with the demethylase LSD1 in embryonic stem cells and is needed for pluripotency. It can also replace SOX2 when somatic cells are reprogrammed to induced pluripotency.
A systematic test of whether histones carrying methyl-lysine analogues behave like natural methylated histones in biochemical reactions.
Principal Investigator · Curriculum vitae
Tenured Professor and PhD Supervisor
School of Life Sciences and Technology, Tongji University
Peng Yang studies how KRAB zinc-finger proteins (KZFPs) recognise DNA and how they control transposable elements, imprinted genes and early embryonic development. As a postdoctoral fellow at the U.S. National Institutes of Health he showed that the KZFP ZFP568 silences a placenta-specific Igf2 transcript and so regulates fetal and placental growth (Science 2017, first author). He also solved, with collaborators, how its eleven-finger array adapts to the shape of DNA (Cell 2018, co-first author).
Since establishing his laboratory at Tongji University in 2018, he has identified human and mouse KZFPs that target the tRNA primer-binding sites of endogenous and exogenous retroviruses, including the PBS-Lys site used by HIV-1. This work, together with a study of embryonic genome activation, appeared in PNAS, Nucleic Acids Research, Science Bulletin and Cell Research, with him as corresponding or co-corresponding author. He has led more than ten million RMB in competitive research funding, including five National Natural Science Foundation of China grants, a National Key R&D Program project and two Shanghai municipal projects.
The lab is now expanding into computational enzyme design and electrochemical biosensors for continuous glucose and ketone monitoring.
