Krüppel-like Factor 11 Differentially Couples to Histone Acetyltransferase and Histone Methyltransferase Chromatin Remodeling Pathways to Transcriptionally Regulate Dopamine D2 Receptor in Neuronal Cells

• Published in: The Journal of biological chemistry Vol. 287; no. 16; pp. 12723 - 12735
• Main Authors: Seo, Seungmae, Lomberk, Gwen, Mathison, Angela, Buttar, Navtej, Podratz, Jewel, Calvo, Ezequiel, Iovanna, Juan, Brimijoin, Stephen, Windebank, Anthony, Urrutia, Raul
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.04.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis Regulatory Proteins; Base Sequence; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Differentiation - physiology; Chromatin - metabolism; Dopamine Receptors; Dopaminergic Neurons - cytology; Dopaminergic Neurons - enzymology; Down-Regulation - physiology; Heterochromatin Protein 1 (HP1); Histone Acetyltransferases - metabolism; Histone Methyltransferases; Histone-Lysine N-Methyltransferase - metabolism; Homeostasis - physiology; Humans; Krüppel-like Factor (KLF); Molecular Sequence Data; Neurites - physiology; Neurobiology; Neurotransmitter Receptors; p300; PC12 Cells; Promoter Regions, Genetic - physiology; Rats; Receptors, Dopamine D2 - genetics; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription Regulation; Transcription, Genetic - physiology; p300; Neurotransmitter Receptors; Heterochromatin Protein 1 (HP1); Transcription Regulation; Krüppel-like Factor (KLF); Dopamine Receptors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.351395

The importance of Krüppel-like factor (KLF)-mediated transcriptional pathways in the biochemistry of neuronal differentiation has been recognized relatively recently. Elegant studies have revealed that KLF proteins are important regulators of two major molecular and cellular processes critical for neuronal cell differentiation: neurite formation and the expression of neurotransmitter-related genes. However, whether KLF proteins mediate these key processes in a separate or coordinated fashion remains unknown. Moreover, knowledge on the contribution of chromatin dynamics to the biochemical mechanisms utilized by these proteins to perform their function is absent. Here we report the characterization of two antagonistic, chromatin-mediated mechanisms by which KLF11, also known as TIEG2 (transforming growth factor-β-inducible early gene 2) and MODY VII (maturity onset diabetes of the young VII), regulates transcription of the fopamine D2 receptor (Drd2) gene. First, KLF11 activates transcription by binding to a distinct Sp-KLF site within the Drd2 promoter (−98 to −94) and recruiting the p300 histone acetyltransferase. Second, Drd2 transcriptional activation is partially antagonized by heterochromatin protein 1 (HP1), the code reader for histone H3 lysine 9 methylation. Interestingly, KLF11 regulates neurotransmitter receptor gene expression in differentiating neuronal cell populations without affecting neurite formation. Overall, these studies highlight histone methylation and acetylation as key biochemical mechanisms modulating KLF-mediated neurotransmitter gene transcription. These data extend our knowledge of chromatin-mediated biochemical events that maintain key phenotypic features of differentiated neuronal cells. Background: Chromatin-mediated events utilized by Krüppel-Like factors in neurons remain undefined. Results: Krüppel-Like factor 11 couples to antagonistic chromatin pathways (p300 versus heterochromatin protein 1) to regulate the dopamine D2 receptor gene. Conclusion: This is the first description of mechanisms underlying Krüppel-like factor-mediated functions in neurons. Significance: This knowledge expands our understanding of chromatin-mediated mechanisms that influence homeostasis in highly specialized cells.