Chemically Induced Proximity (CIP) in Biology and Medicine: The Importance of Being Close.  Several years ago, working with Stuart Schreiber (pictured below), we developed bifunctional small molecules to explore the role of proximity in biology¹. These molecules (such as FK1012) get through the cell membrane and bind to small protein tags that we could add to a protein of interest and simply bring the tagged proteins close to one another as dimers or oligomers as illustrated below on the right.  These studies revealed that induced proximity was a fundamental biophysical principal used by many membrane receptors^1-6 kinases⁷, exchange factors⁸, transcription factors⁹ and epigenetic regulators^10-15.  The realization that chemically induced proximity (CIP) to E3 ligases and then to the proteosome was central to controling protein degradation led our lab to collaborate with Martin Prushy, in Stuart’s lab, to develop bifunctional degraders. Martin’s lab mate Craig Crews extended the concept after starting his own lab at Yale to develop PROTACs¹⁶. Further development by Criag and his colleagues has blossomed into a major new field.  Protein stabilization¹⁷ and localization¹⁸ could also be easily controlled by CIP, In addition, we were able to show that post translational modifications such as phosphorylation or methylation often produced their effects by induced proximity¹⁰. These studies laid the foundation for development of investigative tools and therapeutics that function by induced proximity.

Epigenetic and transcriptional regulation were particularly informative examples of induced proximity.  We made strains of mice (which we called the Chromatin in vivo Assay or CA mice), in which we could use CIP to recruit critical chromatin and epigenetic regulators to specific genetic loci and then measure the minute-by-minute biochemical consequences^10,14.  Simon Braun in the lab, extended these techniques to any genetic locus in a living mouse by CRISPR-facilitated recruitment¹⁹.  Oli Bell and Nathanael Hathaway were able to induce spreading repression by recreating Position Effect Variation at the Oct4 locus¹⁰ and measure its speed along the chromosome^10,20. In cells from the CIA mice we could activate ATP-dependent remodeling complexes and rapidly reverse Polycomb repression thereby providing a molecular understanding of the long mysterious opposition between Trithorax and Polycomb^13,14. Emma Chory (now at Duke University) used this system to demonstrate that the turnover of modified nucleosomes by ATP-dependent chromatin remodels is a general means of propagation of epigenetic marks and a determinant of methylation valence^12,21. Indeed, most aspects of epigenetic and transcriptional regulation could be produced by CIP²¹. These were proof-of-concept experiments for our later development of therapeutics for a variety of human diseases (see next section).

At a practical level, the demonstration that CIP of T cell receptor zeta chain could be used to activate T cells contributed to the development of Chimeric Antigen Receptors for CAR-T therapy¹.  Furthermore, the discovery that the FAS receptor and caspases were activated by induced proximity using FK1012 or rimiducid by David Spencer in our lab and Pete Belshaw in Stuart’s lab led to the development of safety switches for CAR-T therapy^2-4,6.  Finally, modulation of the binding affinity of target proteins by CIP, first developed by Roger Briesewitz in our lab²² is now being used to make better ras inhibitors^23-26, which are presently in clinical trials²⁷.  The Briesewitz approach of affinity modulation by CIP has also led to the development of inhibitors of protein interactions with transcription factors, for example with RIPTACs, which are a subclass of TCIPs^28-30 that inhibit their targets³¹.   Presently there are many drugs under clinical trial that make use of the fundamental mechanism of induced proximity and most major pharmaceutical companies have therapeutic programs using induced proximity with small bifunctional molecules.

Hijacking Cancer Drivers to Activate Cell Death: Killing Cancer with its Cause

Recently we developed a new class of molecules that rewire cancer drivers to activate cell death pathways and thereby deliberately and specifically induce cancer cell death^28-30.  While essentially all pharmaceutical development relies on defining a target of interest and then making an inhibitor to it, we reasoned that small molecules could also be used to hijack or rewire the fundamental circuitry of a cell and then examine the consequences on a minute-by-minute basis to understand fundamental biologic mechanisms or to kill a cancer cell with its driver for therapeutic purposes.  We call this new class of gain-of-function molecules TCIPs or SCIPs for Transcriptional/Epigenetic Chemical Inducers of Proximity or Signaling Chemical Inducers of Proximity.   

Perhaps the most exciting potential of TCIPs or SCIPs might be in developing new treatments and investigative tools for cancer.  During the past 40 years cancer has been shown to be a genetic disease caused by mutations in genes able to autonomously drive the proliferation or spread of the cancer (Such as those shown on the left side of the illustration above) ³². The field of cancer biology now has about 200 or more verified cancer drivers, many of them truncal mutations present in every cancer cell.  During the same period, programmed cell death pathways have been discovered that define our morphology as well as our immune and nervous systems (the right side of the illustration above) ³³.  These two major discoveries lead us to ask if we could use induced proximity to hijack the cancer driver to produce death of the cancer cell (As shown in C above) rather than survival and proliferation.  This rewiring approach has been remarkably effective, quickly producing non-toxic molecules that function at picomolar concentrations to eliminate cancers in mice.   These molecules use only a fraction of the target protein to rewire the cancer driver to activate cell death and therefor lack mechanism-based toxicity that limits conventional inhibitors, degraders, RNAi, RIPTACs and PROTACs.  Because TCIPs actively produce cell death by a dominant gain of function, they have the ability to circumvent secondary drivers or alternative oncogenic pathways.  The first of these molecules is now moving toward clinical development.

Chromatin and Epigenetic Regulation in Development.

Our lab got its start by systematically exploring the signaling pathways by which the antigen receptor on T cells activates genes, like IL2, interferon and others that are essential for and coordinate the immune response. To do this we worked backward from the nucleus, first identifying the sensitive regions of the responding genes, then the transcriptional regulators controlled by the antigen receptor and finally identifying the upstream activators (Ca²⁺, Calcineurin and NFAT) ^34-40. Surprisingly, the pathway through the antigen receptor, Ca²⁺, Calcineurin and NFAT that we defined was present in many cell types and in fact played major roles in the development of neurons^41,42, the vascular system⁴³ the heart^44,45, pancreatic beta cells⁴⁶ and skin. ⁴⁷.  In addition, many of the features of Down Syndrome were due to reduction in signaling by Ca²⁺, Calcineurin and NFAT⁴⁸. Our experiments indicated that the presentation of receptors, like the T Cell Antigen Receptor on the surface of T cells, was accompanied by developmental preparation of the nucleus to receive signals and produce specific responses: one genomic response in T cells, another genomic response in neurons.  We found that these different responses were due to an ATP-dependent chromatin regulatory complex (BAF complexes) related to the fly Brahma complex and the yeast SWI/SNF complex that made different parts of the genome available to signals from a receptor in different cell types^34,49.

Biochemical purification of the defining proteins led to identification of an epigenetic regulatory complex similar to the yeast SWI/SNF complex and the fly Brahma protein complex^49,50.  An immediate answer to the question of specificity emerged when we found that neurons had a specific nBAF complex, with neuron-specific subunits that are not found in any other cell type^51-53.  Remarkably, Andrew Yoo in our lab, found that developmental formation of this neuron-specific complex was due to a triple-negative genetic circuit that could convert human fibroblasts to basal state neurons that could then be specified into many different neuronal subtypes with fate determining transcription factors^54,55.

Human genetic studies showed that the genes encoding these neuron specific complexes were among the most frequently mutated genes in autism and human intellectual disability. This observation lead Wendy Wenderisky in our lab to work with Joe Gleason at UCSD to show that one neuron-specific subunit (BAF53b) was causally related to autism^56-58, unlike many other genes that are only associated with autism. With Rob Malenka and Karl Deisseroth we found that these neural specific BAF subunits execute their function in cells in the dorsal raphe, (known to control social behavior) and even more remarkably, execute their function in adult neurons of the dorsal raphe on a minute-by-minute basis, suggesting that one’s social abilities are being constantly monitored by the nBAF complex⁵⁶. But how does it do this?  How does epigenetic regulation turn into social behavior?  We have only started to approach these questions.

A long-standing mystery in development has been the opposition between the Trithorax proteins and the Polycomb complex.  These two complexes oppose each other’s actions to establish the body plan as shown in the picture on the left and to organize many aspects of the nervous system, yet the mechanism underlying this opposition has eluted understanding.  To approach this question, we developed a strain of mouse and additional technical methods that allows us to rapidly add an epigenetic regulator to any gene in any tissue of the living mouse.  With tough in cheek, we called the mice and the system the Chromatin In vivo Assay, or CIA systems in mice^10,13,14, for interrogating chromatin function in living cells and animals. (I hope in the future, when the name CIA is mentioned, you will think of our remarkable mice and their use for answering all sorts of chromatin associated questions). Using these mice, we were able to measure and define the mechanism of Trithorax-Polycomb opposition for the mammalian BAF complex (flies and worm would almost certainly use the same mechanism). We used CIP to produce proximity of the BAF complex to the highly Polcomb-repressed Oct4 gene in pluripotent cells. To everyone’s surprise we found that the opposition was immediate and occurred by direct eviction of Polycomb repressive complexes and the minute-by-minute loss of the repressive H3K27Me3 mark^13,14.  We are now attempting to understand the molecular details of this essential process.

With the CIA mice we were able to measure for the first time the speed of spreading repression by Position Effect Variation (PEV) mediated by HP1 and H3K9Me9.  PEV was discovered in 1946 by Herman Muller, a finding for which he received the Nobel Prize and refers to the way that repression spreads after DNA recombination leading to a polymorphic phenotype (eye color).  Courtney Hodges, Oli Bell and Nat Hathway in our lab found that repression progressed at average rates of ~0.18 nucleosomes/hr to produce domains of up to 10 kb at the Oct4 locus and that H3K9 methylation laid the foundation for DNA methylation^20,59.  Diana Hargraves and Eric Miller found that the CIP H3K9Me3 system was sufficiently powerful to shut down the Oct4 gene in pluripotent cells⁶⁰.  The use of CIP to recruit the BAF complex also allowed us to demonstrate that pioneer factors, such as Oct4 require the use of the ATP-dependent remodeler to bind DNA, leading to a “assisted loading” hypothesis^60,61.  In the future we would like to better understand the mechanistic underpinnings of this classic developmental process whereby Polycomb and BAF compete to aid in the organization of the body plan.

REFERENCES

1. Spencer, D.M., Wandless, T.J., Schreiber, S.L., and Crabtree, G.R. (1993). Controlling signal transduction with synthetic ligands. Science 262, 1019–1024. 10.1126/science.7694365.
2. Spencer, D.M., Belshaw, P.J., Chen, L., Ho, S.N., Randazzo, F., Crabtree, G.R., and Schreiber, S.L. (1996). Functional analysis of Fas signaling in vivo using synthetic inducers of dimerization. Curr.Biol. 6, 839–847.
3. Freiberg, R.A., Spencer, D.M., Choate, K.A., Duh, H.J., Schreiber, S.L., Crabtree, G.R., and Khavari, P.A. (1997). Fas signal transduction triggers either proliferation or apoptosis in human fibroblasts. J Invest Dermatol 108, 215–219.
4. Freiberg, R.A., Spencer, D.M., Choate, K.A., Peng, P.D., Schreiber, S.L., Crabtree, G.R., and Khavari, P.A. (1996). Specific triggering of the Fas signal transduction pathway in normal human keratinocytes. J Biol Chem 271, 31666–31669.
5. Pruschy, M.N., Spencer, D.M., Kapoor, T.M., Miyake, H., Crabtree, G.R., and Schreiber, S.L. (1994). Mechanistic studies of a signaling pathway activated by the organic dimerizer FK1012. Chem Biol 1, 163–172.
6. MacCorkle, R.A., Freeman, K.W., and Spencer, D.M. (1998). Synthetic activation of caspases: artificial death switches. Proc Natl Acad Sci U S A 95, 3655–3660. 10.1073/pnas.95.7.3655.
7. Graef, I.A., Holsinger, L.J., Diver, S., Schreiber, S.L., and Crabtree, G.R. (1997). Proximity and orientation underlie signaling by the non-receptor tyrosine kinase ZAP70. EMBO J 16, 5618–5628. 10.1093/emboj/16.18.5618.
8. Holsinger, L.J., Spencer, D.M., Austin, D.J., Schreiber, S.L., and Crabtree, G.R. (1995). Signal transduction in T lymphocytes using a conditional allele of Sos. Proc Natl Acad Sci U S A 92, 9810–9814.
9. Ho, S.N., Biggar, S.R., Spencer, D.M., Schreiber, S.L., and Crabtree, G.R. (1996). Dimeric ligands define a role for transcriptional activation domains in reinitiation. Nature 382, 822–826. 10.1038/382822a0.
10. Hathaway, N.A., Bell, O., Hodges, C., Miller, E.L., Neel, D.S., and Crabtree, G.R. (2012). Dynamics and memory of heterochromatin in living cells. Cell 149, 1447–1460. 10.1016/j.cell.2012.03.052.
11. Ni, K., Ren, J., Xu, X., He, Y., Finney, R., Braun, S.M.G., Hathaway, N.A., Crabtree, G.R., and Muegge, K. (2020). LSH mediates gene repression through macroH2A deposition. Nat Commun 11, 5647. 10.1038/s41467-020-19159-0.
12. Chory, E.J., Calarco, J.P., Hathaway, N.A., Bell, O., Neel, D.S., and Crabtree, G.R. (2019). Nucleosome Turnover Regulates Histone Methylation Patterns over the Genome. Mol Cell 73, 61–72 e63. 10.1016/j.molcel.2018.10.028.
13. Kadoch, C., Williams, R.T., Calarco, J.P., Miller, E.L., Weber, C.M., Braun, S.M., Pulice, J.L., Chory, E.J., and Crabtree, G.R. (2017). Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states. Nat Genet 49, 213–222. 10.1038/ng.3734.
14. Stanton, B.Z., Hodges, C., Calarco, J.P., Braun, S.M., Ku, W.L., Kadoch, C., Zhao, K., and Crabtree, G.R. (2017). Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet 49, 282–288. 10.1038/ng.3735.
15. Hodges, H.C., Stanton, B.Z., Cermakova, K., Chang, C.Y., Miller, E.L., Kirkland, J.G., Ku, W.L., Veverka, V., Zhao, K., and Crabtree, G.R. (2018). Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 25, 61–72. 10.1038/s41594-017-0007-3.
16. Burslem, G.M., and Crews, C.M. (2020). Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell 181, 102–114. 10.1016/j.cell.2019.11.031.
17. Gestwicki, J.E., Crabtree, G.R., and Graef, I.A. (2004). Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation. Science 306, 865–869.
18. Klemm, J.D., Beals, C.R., and Crabtree, G.R. (1997). Rapid targeting of nuclear proteins to the cytoplasm. Curr Biol 7, 638–644.
19. Braun, S.M.G., Kirkland, J.G., Chory, E.J., Husmann, D., Calarco, J.P., and Crabtree, G.R. (2017). Rapid and reversible epigenome editing by endogenous chromatin regulators. Nat Commun 8, 560. 10.1038/s41467-017-00644-y.
20. Hodges, C., and Crabtree, G.R. (2012). Dynamics of inherently bounded histone modification domains. Proc Natl Acad Sci U S A 109, 13296–13301. 10.1073/pnas.1211172109.
21. Stanton, B.Z., Chory, E.J., and Crabtree, G.R. (2018). Chemically induced proximity in biology and medicine. Science 359. 10.1126/science.aao5902.
22. Briesewitz, R., Ray, G.T., Wandless, T.J., and Crabtree, G.R. (1999). Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces. Proc Natl Acad Sci U S A 96, 1953–1958.
23. Holderfield, M., Lee, B.J., Jiang, J., Tomlinson, A., Seamon, K.J., Mira, A., Patrucco, E., Goodhart, G., Dilly, J., Gindin, Y., et al. (2024). Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature 629, 919–926. 10.1038/s41586-024-07205-6.
24. Weller, C., Burnett, G.L., Jiang, L., Chakraborty, S., Zhang, D., Vita, N.A., Dilly, J., Kim, E., Maldonato, B., Seamon, K., et al. (2025). A neomorphic protein interface catalyzes covalent inhibition of RAS(G12D) aspartic acid in tumors. Science 389, eads0239. 10.1126/science.ads0239.
25. Schulze, C.J., Seamon, K.J., Zhao, Y., Yang, Y.C., Cregg, J., Kim, D., Tomlinson, A., Choy, T.J., Wang, Z., Sang, B., et al. (2023). Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science 381, 794–799. 10.1126/science.adg9652.
26. Liu, J.O. (2023). Targeting cancer with molecular glues. Science 381, 729–730. 10.1126/science.adj1001.
27. Repity, M.L., Deutscher, R.C.E., and Hausch, F. (2025). Nondegradative Synthetic Molecular Glues Enter the Clinic. ChemMedChem 20, e202500048. 10.1002/cmdc.202500048.
28. Gourisankar, S., Krokhotin, A., Ji, W., Liu, X., Chang, C.Y., Kim, S.H., Li, Z., Wenderski, W., Simanauskaite, J.M., Yang, H., et al. (2023). Rewiring cancer drivers to activate apoptosis. Nature 620, 417–425. 10.1038/s41586-023-06348-2.
29. Sarott, R.C., Gourisankar, S., Karim, B., Nettles, S., Yang, H., Dwyer, B.G., Simanauskaite, J.M., Tse, J., Abuzaid, H., Krokhotin, A., et al. (2024). Relocalizing transcriptional kinases to activate apoptosis. Science 386, eadl5361. 10.1126/science.adl5361.
30. Nix, M.N., Gourisankar, S., Sarott, R.C., Dwyer, B.G., Nettles, S.A., Martinez, M.M., Abuzaid, H., Yang, H., Wang, Y., Simanauskaite, J.M., et al. (2025). A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death. bioRxiv.
31. Raina, K., Forbes, C.D., Stronk, R., Rappi, J.P., Jr., Eastman, K.J., Zaware, N., Yu, X., Li, H., Bhardwaj, A., Gerritz, S.W., et al. (2024). Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies. Cell Chem Biol 31, 1490–1502 e1442. 10.1016/j.chembiol.2024.07.005.
32. Hanahan, D., and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. 10.1016/j.cell.2011.02.013.
33. Strasser, A., O’Connor, L., and Dixit, V.M. (2000). Apoptosis Signaling. Annual Review of Biochemistry 69, 217–245. 10.1146/annurev.biochem.69.1.217.
34. Siebenlist, U., Durand, D.B., Bressler, P., Holbrook, N.J., Norris, C.A., Kamoun, M., Kant, J.A., and Crabtree, G.R. (1986). Promoter region of the IL-2 gene undergoes chromatin structure changes and confers inducibility on Chloramphenicol Acetyltransferase gene during Activation of T cells. Mol Cell Biol 6, 3042–3049.
35. Durand, D.B., Bush, M.R., Morgan, J.G., Weiss, A., and Crabtree, G.R. (1987). A 275 bp fragment at the 5′ end of the IL-2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor. J.Exp Med. 165, 395–407.
36. Durand, D.B., Shaw, J.P., Bush, M.R., Replogle, R.E., Belagaje, R., and Crabtree, G.R. (1988). Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol 8, 1715–1724.
37. Shaw, J.P., Utz, P.J., Durand, D.B., Toole, J.J., Emmel, E.A., and Crabtree, G.R. (1988). Identification of a putative regulator of early T cell activation genes. Science 241, 202–205.
38. Flanagan, W.M., Corthesy, B., Bram, R.J., and Crabtree, G.R. (1991). Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A [see comments]. Nature 352, 803–807.
39. Clipstone, N.A., and Crabtree, G.R. (1992). Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357, 695–697. 10.1038/357695a0.
40. Gallo, E.M., Winslow, M.M., Cante-Barrett, K., Radermacher, A.N., Ho, L., McGinnis, L., Iritani, B., Neilson, J.R., and Crabtree, G.R. (2007). Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature 450, 731–735. nature06305 [pii]

10.1038/nature06305.

41. Graef, I.A., Mermelstein, P.G., Stankunas, K., Neilson, J.R., Deisseroth, K., Tsien, R.W., and Crabtree, G.R. (1999). L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401, 703–708.
42. Graef, I.A., Wang, F., Charron, F., Chen, L., Neilson, J., Tessier-Lavigne, M., and Crabtree, G.R. (2003). Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113, 657–670.
43. Graef, I.A., Chen, F., Chen, L., Kuo, A., and Crabtree, G.R. (2001). Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 105, 863–875.
44. Chang, C.P., Neilson, J.R., Bayle, J.H., Gestwicki, J.E., Kuo, A., Stankunas, K., Graef, I.A., and Crabtree, G.R. (2004). A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell 118, 649–663.
45. Ranger, A.M., Grusby, M.J., Hodge, M.R., Gravallese, E.M., de la Brousse, F.C., Hoey, T., Mickanin, C., Baldwin, H.S., and Glimcher, L.H. (1998). The transcription factor NF-ATc is essential for cardiac valve formation [see comments]. Nature 392, 186–190.
46. Heit, J.J., Apelqvist, A.A., Gu, X., Winslow, M.M., Neilson, J.R., Crabtree, G.R., and Kim, S.K. (2006). Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 443, 345–349.
47. Horsley, V., Aliprantis, A.O., Polak, L., Glimcher, L.H., and Fuchs, E. (2008). NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132, 299–310.
48. Arron, J.R., Winslow, M.M., Polleri, A., Chang, C.P., Wu, H., Gao, X., Neilson, J.R., Chen, L., Heit, J.J., Kim, S.K., et al. (2006). NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441, 595–600.
49. Khavari, P.A., Peterson, C.L., Tamkun, J.W., Mendel, D.B., and Crabtree, G.R. (1993). BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366, 170–174. 10.1038/366170a0.
50. Northrop, J.P., Ho, S.N., Chen, L., Thomas, D.J., Timmerman, L.A., Nolan, G.P., Admon, A., and Crabtree, G.R. (1994). NF-AT components define a family of transcription factors targeted in T- cell activation [see comments]. Nature 369, 497–502.
51. Lessard, J., Wu, J.I., Ranish, J.A., Wan, M., Winslow, M.M., Staahl, B.T., Wu, H., Aebersold, R., Graef, I.A., and Crabtree, G.R. (2007). An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 55, 201–215. 10.1016/j.neuron.2007.06.019.
52. Wu, J.I., Lessard, J., and Crabtree, G.R. (2009). Understanding the words of chromatin regulation. Cell 136, 200–206. 10.1016/j.cell.2009.01.009.
53. Wu, J.I., Lessard, J., Olave, I.A., Qiu, Z., Ghosh, A., Graef, I.A., and Crabtree, G.R. (2007). Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron 56, 94–108. 10.1016/j.neuron.2007.08.021.
54. Yoo, A.S., Staahl, B.T., Chen, L., and Crabtree, G.R. (2009). MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460, 642–646. 10.1038/nature08139.
55. Yoo, A.S., Sun, A.X., Li, L., Shcheglovitov, A., Portmann, T., Li, Y., Lee-Messer, C., Dolmetsch, R.E., Tsien, R.W., and Crabtree, G.R. (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476, 228–231. 10.1038/nature10323.
56. Walsh, J.J., Llorach, P., Cardozo Pinto, D.F., Wenderski, W., Christoffel, D.J., Salgado, J.S., Heifets, B.D., Crabtree, G.R., and Malenka, R.C. (2021). Systemic enhancement of serotonin signaling reverses social deficits in multiple mouse models for ASD. Neuropsychopharmacology 46, 2000–2010. 10.1038/s41386-021-01091-6.
57. Wenderski, W., and Maze, I. (2016). Histone turnover and chromatin accessibility: Critical mediators of neurological development, plasticity, and disease. Bioessays 38, 410–419. 10.1002/bies.201500171.
58. Wenderski, W., Wang, L., Krokhotin, A., Walsh, J.J., Li, H., Shoji, H., Ghosh, S., George, R.D., Miller, E.L., Elias, L., et al. (2020). Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism. Proc Natl Acad Sci U S A 117, 10055–10066. 10.1073/pnas.1908238117.
59. Hathway, N.B.O.H., C.; Miller, E.L.; Neel, D.S. and Crabtree, G.R. (2012). Dynamics and Memory of Heterochromatin in Living Cells. Cell in press.
60. Miller, E.L., Hargreaves, D.C., Kadoch, C., Chang, C.Y., Calarco, J.P., Hodges, C., Buenrostro, J.D., Cui, K., Greenleaf, W.J., Zhao, K., and Crabtree, G.R. (2017). TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nature Structural & Molecular Biology 24, 344–352. 10.1038/nsmb.3384.
61. Voss, T.C., Schiltz, R.L., Sung, M.H., Yen, P.M., Stamatoyannopoulos, J.A., Biddie, S.C., Johnson, T.A., Miranda, T.B., John, S., and Hager, G.L. (2011). Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146, 544–554. 10.1016/j.cell.2011.07.006.