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Heterochromatin Remodeling by CDK12 Contributes to Learning in Drosophila

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Heterochromatin Remodeling by CDK12 Contributes to Learning in Drosophila Heterochromatin remodeling by CDK12 contributes to learning in Drosophila Lixia Pana, Wenbing Xieb,1, Kai-Le Lic, Zhihao Yanga, Jiang Xua, Wenhao Zhangd, Lu-Ping Liua, Xingjie Rena, Zhimin Hea, Junyu Wua, Jin Suna, Hui-Min Weic, Daliang Wanga, Wei Xied, Wei Lic, Jian-Quan Nia,2, and Fang-Lin Sunc,a,2 aSchool of Medicine, Tsinghua University, Beijing 100084, China; bKey Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China; cResearch Center for Translational Medicine at East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200120/200092, China; and dTsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China Edited by Shiv I. S. Grewal, National Institutes of Health, Bethesda, MD, and approved September 29, 2015 (received for review February 15, 2015) Dynamic regulation of chromatin structure is required to modulate Results the transcription of genes in eukaryotes. However, the factors that Cyclin-Dependent Kinase 12 Counteracts Heterochromatin Enrichment contribute to the plasticity of heterochromatin structure are elusive. on Euchromatic Regions. To understand how heterochromatin Here, we report that cyclin-dependent kinase 12 (CDK12), a transcrip- domains are regulated on chromosomes, we intended to screen tion elongation-associated RNA polymerase II (RNAPII) kinase, antag- for factors that affect HP1 distribution in Drosophila polytene onizes heterochromatin enrichment in Drosophila chromosomes. chromosomes. Because kinases play important roles in modu- Notably, loss of CDK12 induces the ectopic accumulation of hetero- lating the cellular localization of their substrates and kinase JIL-1 chromatin protein 1 (HP1) on euchromatic arms, with a prominent has been reported to regulate HP1 binding on chromosomes (12), enrichment on the X chromosome. Furthermore, ChIP and sequencing we performed a pilot transgenic RNAi screen focusing on kinases. analysis reveals that the heterochromatin enrichment on the X The “visible” and consistent cytological localization of HP1 at chromosome mainly occurs within long genes involved in neuronal the chromocenter on giant polytene chromosomes from the functions. Consequently, heterochromatin enrichment reduces the third-instar larvae allows for evaluation of the switch between transcription of neuronal genes in the adult brain and results in a GENETICS Drosophila the heterochromatic and euchromatic domains through immu- defect in courtship learning. Taken together, these results nofluorescence assays. We screened transgenic RNAi lines against define a previously unidentified role of CDK12 in controlling the epi- protein kinases in Drosophila using a salivary gland-specific (SG) genetic transition between euchromatin and heterochromatin and GAL4 (SG-GAL4). Surprisingly, we found substantial accumula- suggest a chromatin regulatory mechanism in neuronal behaviors. tion of HP1 in euchromatic regions in a cyclin-dependent kinase 12 (CDK12) RNAi line (TH00344.N) (Fig. 1A). In addition, epigenetic transition | HP1 | RNAPII C-terminal domain kinase | similar HP1 binding patterns were observed in male and female histone H3 on Lys9 methylation | neuronal function flies after CDK12 knockdown (Fig. S1A), suggesting that this ppropriate regulation of gene transcription is essential Significance Athroughout the life of an organism. In eukaryotes, DNA and histone octamers are assembled into nucleosomes and further compacted into higher-order structures (1). Dynamic changes in Eukaryotic genomes are compacted into chromosomes, in the chromatin architecture affect gene transcription in many aspects which heterochromatin is generally considered to be distinct from euchromatin in chromosomal packaging levels and loca- of developmental and physiological processes, such as neural plas- tions. In Drosophila, heterochromatin is mainly found in peri- ticity, memory formation, and cognition (2, 3). Eukaryotic genomes centric and telomeric regions. In this study, we show that are composed of two basic forms, euchromatin and hetero- heterochromatin landscapes that interspersed in euchromatic chromatin, which are originally characterized by their cytological arms are counteracted by CDK12, a major RNA polymerase II chromatin packaging levels. Euchromatic regions are gener- C-terminal domain kinase. After the depletion of CDK12, het- ally associated with a relatively open chromatin configuration erochromatin enrichment can be observed on euchromatic and mainly contain transcriptionally active genes, whereas het- arms, especially on the X chromosome, which leads to tran- erochromatin is highly compacted and less accessible to the scriptional attenuation in targeted genes and defects in neuro- transcriptional machinery (4). Drosophila heterochromatin is nal functions. Our findings provide insights into the regulation mainly localized at the pericentric and subtelomeric regions and of heterochromatin domain in the natural chromosomal con- enriched for methylation of histone H3 on Lys9 (H3K9me), text and suggest a chromatin regulatory role of CDK12 in neu- which provides a docking site for heterochromatin protein 1 ronal functions. (HP1) (5, 6), a highly conserved protein involved in hetero- chromatin formation (7). Previous studies also show that HP1 Author contributions: L.P., J.-Q.N., and F.-L.S. designed research; L.P. and K.-L.L. per- and H3K9me associate with a subset of loci on euchromatic re- formed research; Z.Y., L.-P.L., X.R., Z.H., J.W., J.S., H.-M.W., D.W., W.L., and J.-Q.N. con- gions, and they presumably serve to fine tune the level of gene tributed new reagents/analytic tools; L.P., Wenbing Xie, K.-L.L., J.X., W.Z., Wei Xie, W.L., J.-Q.N., and F.-L.S. analyzed data; and L.P., J.X., J.-Q.N., and F.-L.S. wrote the paper. transcription (8–10). One significant question that comes up is The authors declare no conflict of interest. how the chromatin structure is dynamically regulated to impact expression of genes in complex neuronal processes, such as This article is a PNAS Direct Submission. learning and memory. Our earlier study on chromatin domain Freely available online through the PNAS open access option. mapping of chromosome 4 suggests that heterochromatic do- Data deposition: The data reported in this paper have been deposited in the Gene Ex- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE63011). mains may be regulated by the activities of RNA polymerase II “ ” 1Present address: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The (RNAPII) complexes, which form a barrier to prevent het- Johns Hopkins University School of Medicine, Baltimore, MD 21287. erochromatin spreading and transcriptional gene silencing (11). 2 To whom correspondence may be addressed. Email: [email protected] or flsun@mail. However, the mechanism underlying such a mode of regulation tsinghua.edu.cn. and the consequence on reprogrammed transcription remain to This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. be investigated. 1073/pnas.1502943112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1502943112 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 and E). Moreover, we observed heterochromatin enrichment in fat body cells as indicated by H3K9me2 on CDK12 depletion (Fig. S2 F and G), suggesting that this phenomenon is preserved between dif- ferent cell types. Taken together, these results show that CDK12 is a previously unidentified regulator for counteracting heterochromatin enrichment on euchromatic arms in Drosophila. Heterochromatin Enrichment Triggered by Loss of CDK12 Primarily Occurs on the X Chromosome. Consistent with previous reports that the X chromosome is a preferential target for heterochro- matin enrichment (12, 16), the accumulation of HP1 induced by CDK12 depletion was prominent on the X chromosome marked by acetylation of histone H4 on Lys16 in males (Fig. 2A). However, the loss of CDK12 driven by SG-GAL4 remarkably reduced the size of the salivary gland, increasing the difficulty in precisely mapping the distribution of HP1 on the X chromosome. Thus, we introduced tub-GAL80ts, a temperature-sensitive in- hibitor of GAL4, for controlling GAL4 activity. At 25 °C, GAL80 Fig. 1. Depletion of CDK12 triggers heterochromatin enrichment on eu- activity is partially inhibited and allows a low level of GAL4/UAS chromatic arms. (A and B) HP1 and H3K9me2 spread to euchromatic arms activation, and the size of the salivary gland was found to be com- after CDK12 knockdown. Polytene chromosomes were squashed and stained parable with that in control. We found that HP1 exhibited a with (A) anti-HP1 and (B) anti-H3K9me2. The relative fluorescence intensities prominent distribution pattern on the X chromosome (Fig. 2B and of HP1 and H3K9me2 on the euchromatic arms based on raw data are shown Fig. S2H). A similar binding pattern was observed for H3K9me2 in Right. Error bars indicate SD (n = 3). *P < 0.05; ***P < 0.001. (C) Western blot results showing that CDK12 depletion has no obvious effect on the level (Fig. S2I). We then mapped HP1 signals to multiple regions on the of HP1 or H3K9me2. Whole-tissue extracts were prepared from third-instar X chromosome and found that HP1 mainly associated with band larvae. Antibodies specific for CDK12, HP1, and H3K9me2 were used. Anti- regions rather than interbands (Table S1). Band regions are shown bodies against
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