The internet is full of lectures and interviews featuring scientists who made groundbreaking discoveries. Below, I have listed key topics in chromatin and gene regulation.
Please note that this is not intended to be a comprehensive review. Many important scientists and their groundbreaking work are not readily available in talk or interview formats online.
[SPECIFICITY]
- Francois Jacob (The Central Dogma, Gene Regulation) YouTube
- How do bacteria respond to different sugar sources? How does a dormant virus begin replicating and exit its host? These fundamental questions in gene regulation led François Jacob to realize that, at their core, they represent the same regulatory principles. While I will focus on eukaryotic gene regulation through chromatin modification, I had to begin with Jacob and Monod, whose work laid the foundation for the field.
To fully appreciate this interview, a background in early molecular biology experiments is helpful. However, it is rare to find discussions that cover the operon model, the PaJaMa experiment, and the discovery of mRNA by himself.
- Mark Ptashne: Genetic Switches YouTube
- Jacob and Monod provided genetic evidence for the existence of a repressor in gene regulation. It was Mark Ptashne and Walter Gilbert who later isolated the repressor and demonstrated its sequence-specific DNA-binding properties. At the time, scientists debated which biomolecule could provide such specificity - RNA seemed more likely than protein, as it could base-pair with target DNA. Ptashne and Gilbert’s experiments shifted this perspective, establishing the concept of sequence-specific DNA-binding proteins and their role in gene regulation. While this lecture does not focus on their early experiments, it is still well worth watching.
- Robert Tjian: 1) Introduction to Transcription YouTube / 2) Gene regulation: Why so complex? YouTube
- Now, moving to eukaryotes - Bob Tjian discusses the purification of Sp1, the first human transcription factor identified as a sequence-specific 'eukaryotic' DNA-binding protein. In the following lecture, he explores chromatin and general transcription factors, laying the groundwork for understanding eukaryotic gene regulation. This marks the beginning of a more complex exploration into how gene expression is controlled in eukaryotic systems.
[NUCLEOSOMES]
- Roger Kornberg: The Structural History of RNA Polymerase Transcription Machinery YouTube
- Between 13:30 min and 30:00 min: he describes the discovery that the histone octamer with wrapped DNA as a fundamental unit of the chromatin structure by forming nucleosomes. Now, it seems obvious that H3, H4, H2A, and H2B form an octamer, but people were not sure at the time whether these proteins were randomly sticking to DNA or if there was any order. There are probably a dozen lectures by Roger Kornberg on YouTube, but this one describes the history in the most detail.
To be updated. (May 30, 2025)
Below, I listed relevant background reading material for our lab's work on canonical PRC1 in spermatogenesis (last updated 2024).
Polycomb biology
- Nucleosome compaction as a regulatory mechanism during development, Bob Kingston, CSHL Keynote (2016) YouTube
- Bob is my postdoctoral advisor. His talk was a while ago, but it still provides a relevant background for our lab's current thinking on the PRC1 function.
- The molecular principles of gene regulation by Polycomb repressive complexes, Blackledge and Klose (2021) Nat Rev Mol Cell Biol.
- This is my favorite recent review on the molecular mechanism of the Polycomb function.
- Context-specific Polycomb mechanisms in development, Kim and Kingston (2022) Nat Rev Genet.
- Bob and I tried to illustrate how the core Polycomb mechanisms are modified by changing its subunits and how those different complexes are utilized and repurposed in diverse biological contexts.
- Cell type-specific role of CBX2 and its disordered region in spermatogenesis, Kim, ..., Kingston (2023) Genes Dev.
- This is my postdoctoral work, characterizing CBX2, a component of cPRC1, function in spermatogenesis. It will be directly relevant to the lab's project in CBX7 in spermatogenesis.
- Compaction of chromatin by diverse Polycomb group proteins requires localized regions of high charge, Grau, ..., Kingston (2011) Genes Dev.
- This paper showed the chromatin compaction activity of CBX components of cPRC1. It also identified basic residues (Lysine, Arginine), and their positive charge are critical for the compaction activity.
- Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells, Morey, ..., Di Croce (2012) Cell Stem Cell.
- This is one of the first papers showing CBX paralog switching during cellular differentiation (mouse embryonic stem cell differentiation).
- SAM domain polymerization links subnuclear clustering of PRC1 to gene silencing, Isono, ..., Koseki (2013) Dev Cell.
- This paper demonstrates the cellular and organismal function of the 'structural' activity of cPRC1 driven by the polymerization activity of the PHC subunit. One of my favorite Polycomb papers.
- List of landmark discoveries in the Polycomb and Trithorax field, Giacomo Cavalli Cavalli Lab Webpage
- For further reading - Giacomo Cavalli has an excellent list of landmark papers. Knowing the history of the field is as important as being up to date on the recent discoveries.
Mouse spermatogenesis & gene regulation
- Spermatogenesis: The Commitment to Meiosis, Michael Griswold, (2016) Physiol Rev.
- This review covers spermatogonial stem cells entering meiosis with the retinoic acid signal.
- Deciphering the mitotic and meiotic phases of spermatogenesis in the mouse, Katherine Romer, (2016) Doctoral thesis, MIT
- Chapter 1, Introduction: The first two parts, "Germ cell specification and differentiation of male and female gametes" and "Spermatogenesis," give a good overview of primordial germ cells to sperm differentiation.
- Gene regulation during meiosis, Gao, Qin, and Schimenti, (2024) Trends Genet.
- A timely review of gene regulation focused on mammalian male meiosis.
- Staging of Mouse Seminiferous Tubule Cross-Sections, Ahmed and de Rooij, (2009) Methods Mol Biol.
Assessment of Spermatogenesis Through Staging of Seminiferous Tubules, Meistrich and Hess, (2013) Methods Mol Biol.
- It is critical to understand the cellular composition of the seminiferous tubules in different stages to evaluate the differentiation process in mice.
- Guidebook: Laboratory Mouse and Rat Colony Management, Pritchett-Corning, ..., Elder (2015) Charles River Laboratories
- This is a helpful guidebook for anyone who begins to work with mice.
Below, I listed relevant background reading material for our lab's work on Kumgang-CHD4 in fly spermatogenesis (last updated, 2024).
Gene regulation by Kumgang-like ZFPs and CHD4
- Blocking promiscuous activation at cryptic promoters directs cell type-specific gene expression, Kim, ..., Fuller (2017) Science
- Discovery of Kumgang and its role in cryptic promoter silencing together with CHD4.
- Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis, Gómez-del Arco, ..., Georgopoulos (2010) Immunity
- IKAROS is a Kumgang-like ZFP that interacts with CHD4. This paper shows that the loss of IKAROS results in the expression of overactive Notch1 protein from an alternative promoter, driving leukemogenesis. I like this paper as I see parallels to Kumgang-mediated cryptic promoter suppression.
- The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression, Bornelöv, ..., Hendrich (2018) Mol Cell
The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment, Burgold, ..., Hendrich (2019) EMBO J
- The experiments in these papers are very nicely done. However, it is still difficult to clearly explain what the CHD4-containing complex does, which may indicate the main function is suppression of 'noise.' A lot to think about in comparison to the kumgang loss transcriptional phenotype.
Fly spermatogenesis & gene regulation
- Lifestyle choices: Self-renewal, proliferation, and differentiation in an adult stem cell lineage, Minx Fuller, GSA Medal lecture (2022) YouTube
- Minx is my PhD advisor. She gave a nice overview of some of her scientific discoveries using fly spermatogenesis as an adult stem cell model.
- Functional analysis of the promoter regions of de novo genes_090 & 074 in Drosophila melanogaster and in vitro Topi C-terminal DNA interaction by SELEX, Shrinivas Dighe (2020) Doctoral thesis, Cardiff University
- Chapter 1.1 to chapter 1.4 nicely describes fly spermatogenesis and gene regulation in post-mitotic male germ cells.
- Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements, Lu, ..., Fuller (2020) Genes Dev.
- It has been known that fly testis-specific gene expression was regulated by short (>300bp) sequences close to their promoters. By performing ATAC-seq and CAGE-seq, Dan performed beautiful analyses of characterizing the promoter-proximal elements.
- Genetics on the Fly: A Primer on the Drosophila Model System, Hales, ..., Roberts (2015) Genetics
- A good overview of Drosophila as an experimental model system.