Abstract
Transcription factors MITF and PU.1 collaborate to increase expression of target genes like cathepsin K (Ctsk) and acid phosphatase 5 (Acp5) during osteoclast differentiation. We show that these factors can also repress transcription of target genes in committed myeloid precursors capable of forming either macrophages or osteoclasts. The direct interaction of MITF and PU.1 with the zinc finger protein Eos, an Ikaros family member, was necessary for repression of Ctsk and Acp5. Eos formed a complex with MITF and PU.1 at target gene promoters and suppressed transcription through recruitment of corepressors CtBP (C-terminal binding protein) and Sin3A, but during osteoclast differentiation, Eos association with Ctsk and Acp5 promoters was significantly decreased. Subsequently, MITF and PU.1 recruited coactivators to these target genes, resulting in robust expression of target genes. Overexpression of Eos in bone marrow-derived precursors disrupted osteoclast differentiation and selectively repressed transcription of MITF/PU.1 targets, while small interfering RNA knockdown of Eos resulted in increased basal expression of Ctsk and Acp5. This work provides a mechanism to account for the modulation of MITF and PU.1 activity in committed myeloid progenitors prior to the initiation of osteoclast differentiation in response to the appropriate extracellular signals.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Acid Phosphatase / genetics
-
Acid Phosphatase / metabolism
-
Animals
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism*
-
Cathepsin K
-
Cathepsins / genetics
-
Cathepsins / metabolism
-
Cell Differentiation / physiology
-
DNA-Binding Proteins
-
Gene Expression Regulation, Developmental*
-
Humans
-
Isoenzymes / genetics
-
Isoenzymes / metabolism
-
Mice
-
Microphthalmia-Associated Transcription Factor / genetics
-
Microphthalmia-Associated Transcription Factor / metabolism*
-
Myeloid Progenitor Cells / cytology
-
Myeloid Progenitor Cells / physiology*
-
NIH 3T3 Cells
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / metabolism*
-
Osteoclasts / physiology*
-
Promoter Regions, Genetic
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
RANK Ligand / genetics
-
RANK Ligand / metabolism
-
RNA, Small Interfering / metabolism
-
Repressor Proteins / genetics
-
Repressor Proteins / metabolism
-
Signal Transduction / physiology
-
Tartrate-Resistant Acid Phosphatase
-
Trans-Activators / genetics
-
Trans-Activators / metabolism*
-
Zinc Fingers
Substances
-
Carrier Proteins
-
DNA-Binding Proteins
-
Isoenzymes
-
Microphthalmia-Associated Transcription Factor
-
Mitf protein, mouse
-
Nerve Tissue Proteins
-
Proto-Oncogene Proteins
-
RANK Ligand
-
RNA, Small Interfering
-
Repressor Proteins
-
Tnfsf11 protein, mouse
-
Trans-Activators
-
Zfpn1a4 protein, mouse
-
proto-oncogene protein Spi-1
-
ACP5 protein, human
-
Acid Phosphatase
-
Acp5 protein, mouse
-
Tartrate-Resistant Acid Phosphatase
-
Cathepsins
-
CTSK protein, human
-
Cathepsin K
-
Ctsk protein, mouse